Hypertrophy

Hypertrophy
Hypertrophy is an increase in muscular size. Research comparing the

effects of training programs over time can help identify how best to
produce hypertrophy.
If you have some resistance-training experience, using higher training
volume, training more regularly while spreading volume over the week,
and performing more eccentric muscle actions may lead to greater
hypertrophy.
If you have little resistance-training experience, lifting heavier loads
(>65% of 1RM), training closer to muscular failure, using higher training
volume, and performing eccentric muscle actions when using
variable resistance may lead to greater hypertrophy.
CONTENTS
Click on the links below to jump down to the relevant section of the page:
1.
Summary
2.
Relative load (percentage of 1RM)
3.
Volume
4.
Muscular failure
5.
Frequency (whole body or split)
6.
Rest period duration
7.
Range of motion
8.
Bar speed (time under tension)
9.
Muscle action (variable)
10. Muscle action (constant load)

11. Periodization type
12. Mechanisms of hypertrophy
13. Genetics and hypertrophy
14. References
-
SUMMARY
PURPOSE
This section provides the background to hypertrophy, including the
various different measurement methods. It also summarizes the current
best evidence for structuring a resistance training program for
hypertrophy.
CONTRIBUTORS
To see the contributors to this page, please click here. To provide feedback,
please click here.
BACKGROUND
Introduction
Hypertrophy is an increase in muscle size. Hypertrophy is thought to arise from a
sustained excess of muscle protein synthesis over muscle protein breakdown over
a period of time, leading to net protein accretion.
Measuring hypertrophy
Hypertrophy is most commonly measured by muscle cross-sectional area (CSA),
volume, limb girth, or lean body mass. Changes in muscular CSA or volume are
most commonly measured using magnetic resonance imaging (MRI) scans,
computed tomography (CT) scans or ultrasonography. Girth is measured using a
tape measure and is rarely now used in comparison with more sophisticated
methods. Changes in lean body mass (strictly fat-free mass) are most commonly
measured using dual-energy X-ray absorptiometry (DEXA) scans or Bod Pod
analysis. The exact measurement method used for hypertrophy may be
important, as different methods have been found to produce different results
when comparing training variables (Weiss et al. 2000).
Importance of hypertrophy
Hypertrophy is desirable for both aesthetic and functional purposes. While most
people associate the deliberate acquisition of additional muscle mass with
bodybuilders, hypertrophy is also very important for athletes participating in
strength sports as it contributes to performance. For example, Brechue et al.

(2002) found that both fat-free mass and muscular CSA at individual sites
were very good predictors of powerlifting ability. Hypertrophy is also important for
elderly people, as low levels of muscle mass are strongly correlated with a loss of
functional independence and mobility and an increased risk of disability and
functional impairment (Janssen et al. 2002; Janssen et al. 2004; Visser et al.
2005; Delmonico et al. 2007).
Relationship between muscle mass and strength

Muscle mass appears to be important for athletic performance and for function in
the elderly because of its close association with strength (Alway et al.
1980; Maughan et al. 1983; Maughan et al. 1983a; Schantz et al. 1983; Sale et al.
1987). Increasing muscular CSA is thought to lead to increased strength by
enlarging the size (and therefore the force-producing capacity) of individual
muscle fibers. However, early long-term studies were not able to
identify correlations between the gains in muscular strength and size that
resulted from resistance training programs (e.g. Davies et al. 1988). It was
thought that this arose because of the large inter-individual variability in strength
and size gains subsequent to a resistance training program (Hubal et al. 2005;
Bamman et al. 2007; review by Timmons, 2011), although why the variability
should be different for each was never clear. More recently, Erskine et al. (2014)
reported that increases in muscle volume of the elbow flexors are indeed strongly
correlated with increases in maximum voluntary isometric contraction force. It
may therefore be the cases that the measurement methods used affected the
correlations and that volume is able to capture more of the change in muscular
size than CSA.
It is important to note that the change in size (and therefore shape) of a muscle
subsequent to resistance training also has a small effect on the muscle moment
arm, which could also enhance strength (Sugisaki et al. 2014), particularly in
larger muscles.
Training methods for hypertrophy
A great deal of research has been performed exploring the role of resistance
training for hypertrophy (see reviews by Tan, 1999; Hunter et al. 2004; Wernbom
et al. 2007; Adams and Bamman, 2012). However, there are also indications that
aerobic exercise can produce a degree of hypertrophy in some muscle groups and
in some populations (see reviews by Ozaki et al. 2013; Konopka and Harber,
2014). Additionally, a relatively novel method of training called Blood Flow
Restriction (BFR) training has been the subject of considerable research in recent
years (see reviews by Pope et al. 2013; Pearson and Hussain, 2014). This
technique can be used with either resistance training or with aerobic exercise
methods to produce hypertrophy (see reviews by Abe et al. 2012; Ozaki et al.
2013).
Current guidance for hypertrophy

There is no shortage of current guidance for producing hypertrophy. This guidance
ranges from advice from expert strength coaches based on their
personal observations (level 4 evidence) through to research-based position
stands (levels 1 3 evidence) produced by leading institutions, such as
the American College of Sports Medicine (Kraemer et al. 2002; ACSM, 2009).
However, these formal position stands for producing muscular adaptations,
including hypertrophy, have been criticized (Carpinelli, 2004; Carpinelli, 2009) on
the basis that they fail to cite enough evidence from long-term trials to
support each recommendation made regarding individual program variables but
rather rely heavily upon tradition (the importance of long-term trials is explained
below). Interestingly, the most fierce criticism for the ACSM position stand in 2002
came from a researcher who may have originally been a member of the review
group for the position stand (Carpinelli, 2004; Fisher and Steele, 2012).
Unsurprisingly therefore, more recent attempts have been made to provide
evidence-based guidance, using solely the long-term trials by individual groups of
researchers (Fisher et al. 2011; Fisher et al. 2013) and these provide a different
perspective on those aspects of a resistance training program are important for
maximizing hypertrophy by removing the elements that are only supported
by tradition.
Long-term trials measuring hypertrophy

Since hypertrophy is a long-term outcome of resistance training, the best
evidence for the type of program that leads to the greatest hypertrophy must
come primarily from long-term trials that measure increases in muscle mass,
volume, or CSA. This is because such trials provide a direct measurement of
hypertrophy, rather than an indirect one. The most relevant long-term trials for
determining how best to structure a resistance training program are those that
compare the effects of two or more different training program variables on
hypertrophy. Training program variables include relative load (percentage of
1RM), volume, proximity to muscular failure, frequency (whole body or split), rest
period duration, range of motion, bar speed (time under tension), muscle action
(variable), muscle action (constant load), and periodization type.
Outside of the research literature, training program variables are almost never
compared in a controlled environment in terms of how much hypertrophy they
produce. On the one hand, it is very common for popular training programs to be
observed to be effective for certain, self-selected populations. On they other
hand, they are never assessed even informally in comparison with other
programs. Therefore, it is very unclear even at the anecdotal level whether
changing an aspect of the program (such as the number of sets or the frequency)
would lead to better or worse results for the majority of lifters.
Short-term trials measuring hypertrophy

Where long-term trials exploring the effects of a training program variable on
hypertrophy do not exist, information can be gathered from short-term (acute)
trials that measure indirect measures of hypertrophy. Such indirect measures
include changes in markers of the processes that are thought to lead to
hypertrophy, including molecular signalling pathways and muscle protein
synthesis. Ideally, any indirect measure used as evidence for training program
variables should first be shown to be well-correlated with hypertrophy in longterm trials. As will be seen later, this is problematic, as few indirect measures
have been found that display strong correlations. Finally, care should be taken
when interpreting the findings of such short-term trials and they should never be
allowed to displace the findings of long-term trials, as they are a secondary level
of evidence.
Lay-out of this hypertrophy review

This review of hypertrophy is structured around the analysis of groups of longterm trials that have explored the effects of specific, individual training program
variables (such as relative load, volume, proximity to muscular failure, frequency,
rest periods, range of motion (ROM), bar speed (time under tension), muscle
action, and periodization type. Each section reviews the literature on the basis of
set selection criteria designed to make sure that the included studies present the
most fair set of circumstances for investigating that particular training program
variable.
-
SUMMARY EVIDENCE FOR HYPERTROPHY

(TRAINED)
Training variable
Research quantity
Confi
dence
Long-term study findings for hypertrophy
Relative load
No research
available
Volume
Few studies
Low
Multiple sets for volume may cause hypertrophy
Muscular failure
No research
available
Frequency
Few relevant
studies
Low
Higher volume-matched frequency may cause hypertrophy
Rest periods
Few relevant
studies
Low
No effect
Range of motion
No research
available
Bar speed
No research
available
Muscle action
(variable load)
Few relevant
studies
Low
Eccentric may cause hypertrophy than concentric
Muscle action
(constant load)
Few relevant
studies
Low
Periodization vs. no
periodization
Few relevant
studies
Moder
ate
No difference
Non-linear vs. linear

periodization
Few relevant
studies
Moder
ate
No difference
Linear vs. reverse
Few relevant
Low
Linear periodization may cause hypertrophy than reverse linear
Training variable
Research quantity
linear
studies
Confi
dence
SUMMARY EVIDENCE FOR HYPERTROPHY

(UNTRAINED)
Training variable
Research quantity
Confidenc
e
Relative load
Several relevant
studies
Moderate
Heavier loads (<15RM) may cause hypertrophy than light loads
Volume
Many relevant studies
Moderate
Multiple sets for volume may cause hypertrophy
Muscular failure
Few relevant studies
Moderate
Closer to muscular failure may cause hypertrophy
Frequency
Low
Unclear
Rest periods
Low
Unclear
Range of motion
Moderate
Larger ROM may cause hypertrophy than shorter ROM
Bar speed
Several relevant
studies
Low
Unclear
Muscle action
(variable load)
Several relevant
studies
Moderate
Muscle action
(constant load)
Several relevant
studies
Moderate
No difference between eccentric and concentric
Periodization vs.
no periodization
Low
Periodization may cause hypertrophy
Non-linear vs.
linear
periodization
Low
Non-linear may cause hypertrophy
CONCLUSIONS FOR HYPERTROPHY

For trained individuals, multiple sets for more volume, a higher volumematched frequency, and performing eccentric muscle actions might increase
hypertrophy.
For untrained subjects, heavier loads (>15RM), multiple sets for more volume,
going closer to muscular failure, larger range-of-motion, performing eccentric
muscle actions when using variable resistance might increase hypertrophy.
Back to top Down to references

RELATIVE LOAD (PERCENTAGE OF 1RM)
PURPOSE
This section explores whether training with a conventionally heavy load

of <15RM is more effective than training with a much lighter load of
>15RM for hypertrophy. This is achieved by looking at long-term studies
that compare different programs of training with heavy and light
relative loads for increasing muscular mass or size.
-
BACKGROUND
Definitions
Relative load (percentage of 1RM)
Resistance training exercises can be performed with any load. The weight lifted
may range from a load that can be lifted only once to loads that can be lifted a
great many times. Since the absolute load (in kg or lbs) that an individual can lift
varies greatly from one person to the next, it is conventional in resistance training
programs to use percentages of one repetition maximum (1RM) when specifying
the loads to be used.
Percentage of 1RM is sometimes referred to as intensity. However, as various
reviewers have observed [Fisher and Smith (2012), Steele (2013), Fisher and
Steele (2014), and Schoenfeld (2014)], this term is ambiguous as it could be
taken to imply a reference to effort that is not intended. Effort may not be the
same as percentage of 1RM, particularly where inter-individual differences exist in
respect of the number of repetitions that can be performed at a given load. For
the sake of clarity, alternative suggestions have been made regarding
terminology, including intensity of load and relative load.
Heavy, moderate and light relative loads

The exact definitions of heavy, moderate and light relative loads differ
substantially between research articles. In the study of hypertrophy, it is very
common to see a dichotomy between heavy and light loads, where heavy
comprises both heavy and moderate loads. In such cases, the dividing line
between heavy and light is defined variously by reviewers as >50% of 1RM
(Schoenfeld, 2013), >60% of 1RM (Schoenfeld, 2013), >65% (McDonagh and

Davies, 1984; Schoenfeld, 2010) or >70% (Spiering et al. 2008; ACSM, 2009).
Popular usage
Most resistance training programs involve relative loads that are >50% of 1RM
and in most cases are also >60 65% of 1RM. Indeed, the majority of individuals
performing any kind of resistance training appear to use loads heavier than
>15RM most of the time. There seem to be few groups of people outside of
research institutions who would consider performing a resistance training
program for the purposes of hypertrophy with loads lighter than this except very
rarely, and for variety.
Literature usage
Researchers have recently become very interested in the extent to which heavy
and light relative loads differ in their ability to produce meaningful hypertrophy. In
The interest in the use of light relative loads seems to have come about through
the success of blood flow restriction (BFR) training. BFR training involves the use
of light relative loads in combination with a restrictive cuff to reduce venous
return from a muscle. Long-term trials of BFR training have found that it can
produce similar increases in muscle mass as conventional heavy relative load
training (see review by Pope et al. 2013).
-
MECHANISMS OF HYPERTROPHY IN RELATION TO

RELATIVE LOAD
[Read full mechanisms section instead]
Conceptual basis for hypertrophy

Mechanical loading (more detail)
The most common stimulus for hypertrophy is the application of mechanical
loading. There are two ways in which a greater relative load might be expected to
lead to a greater mechanical loading effect than a lighter relative load and
thereby create a larger hypertrophic stimulus. Firstly, a greater relative load is

heavier. Secondly, according to the force-velocity relationship, when greater
absolute moment is generated at a joint, the angular velocity of that joint must be
lower (so long as maximal bar speeds are used). As a result of this relationship,
higher relative loads require slower bar speeds and longer repetition durations.
Therefore, a higher relative load might be expected to lead to the activation of a
number of motor units for a longer period of time.
it is generally assumed that the hypertrophic response to the magnitude of the
mechanical loading (as expressed by relative load) is non-linear insofar as there
appears to be a definite threshold below which no hypertrophy can occur (see
review by Schoenfeld, 2013) and a threshold above which little or no further
hypertrophy occurs in response to increasing relative load. The existence of
a threshold of relative load below which no meaningful stimulus for hypertrophy
will occur has been assumed largely upon the empirical observation that people
generally do not experience hypertrophy from carrying out activities of daily living
unless such tasks represent a significant challenge to them, as they can do for
frail, elderly populations. However, it has also been the subject of extensive
review (Schoenfeld, 2013).
Metabolic stress (more detail)

A secondary stimulus for hypertrophy is thought to be exercise-induced metabolic
stress (see reviews by Schoenfeld, 2010; Schoenfeld, 2013). There is a clear
mechanism by which greater numbers of repetitions, as are typically performed
during sets with low-to-moderate relative loads could lead to greater metabolic
stress and acute cellular hydration than sets performed with high relative loads,
as muscular contractions above a certain threshold of maximum voluntary
isometric contraction force prevent venous return. Since metabolic stress arises
primarily from the prevention of venous return and the consequent buildup of
metabolites within the muscle, longer-duration sets with low-to-moderate relative
loads would be expected to lead to greater metabolic stress and consequently
greater hypertrophy, so long as all other factors remained constant.
The relative load at which muscular contractions prevent venous return or
even occlude blood flow completely is of great interest in the context of metabolic
stress. The effect of relative load on occlusion seems to vary between muscles
(Bonde-Petersen et al. 1975; Sadamoto et al. 1983) and between individuals of
different strength levels (Barnes 1980), with stronger individuals achieving
occlusion at much lower relative loads. Some researchers have assumed that 40%
of MVC is sufficient to restrict muscle blood flow (Tanimoto et al. 2008) while 50%
of 1RM is often presented as a rule of thumb for a threshold above which
muscular contractions in the prime movers are strong enough to stop
circulation (Allen et al. 2008). Thus, >50% of 1RM is of particular interest for
researchers and is often used to compare heavy and light loads.
In summary, a higher relative load might be effective than a low relative
load for hypertrophy on the basis that the tensile force in the muscle is
larger in magnitude and may last for a longer period of time, assuming
bar speeds are maximal. Whether this relative load needs to be greater
only than a certain threshold or whether there is a dose-response effect
is unclear. However, a moderate relative load might be more effective
than a high relative load where volume is matched because it
permits increased metabolic stress.
Read more about mechanisms
-
Molecular signalling for hypertrophy

There are conflicting results from studies comparing the molecular
signalling responses between heavy and light relative loads. Some
studies indicate that molecular signalling responses are greater with
heavier loads but other studies show no effect.
The following table sets out studies that have compared molecular signalling
responses for hypertrophy between conditions with different relative loads.
Study
Comparison
Pathway
Population
Finding
Martineau
(2001)
7 protocols ranging from

226 655g of tension
MAPK
Rodent model
Linear relationship between p54 JNK phosphorylation and
Eliasson
(2006)
Maximal vs. sub-maximal

eccentric muscle actions
mTOR
10 untrained males
Maximal displayed greater increases in the phosphorylatio

mTOR or Akt
Wilborn
(2009)
High load (4 sets of 810

repetitions with 80 85%
of 1RM) vs. moderate load
Satellite
cells
13 recreationally active but

untrained males
No difference in mRNA expression of myogenic regulatory
Study
Comparison
Pathway
Population
Finding
(4 sets of 1820
of 1RM)
Kumar
(2009)
High load (6 sets of

3 repetitions with 90% of 1
RM), vs. moderate load (3
sets of 8 9 repetitions
with 6075% of 1RM)
Two groups (25 each) of

healthy, young (24 6
years) and old (70 5
years) males
mTOR
Burd
(2010a)
Muscular failure with 90%

of 1RM (heavy to failure),
muscular failure with 30%
of 1RM (light to failure),
and 30% of 1RM (light)
work-matched to the 90%
of 1RM condition
MAPK
and
mTOR

untrained males
Light to failure displayed increased phosphorylation of Erk
Holm
(2010)
Light load (10 sets of 36

repetitions with 16% of
1RM) vs. heavy load (10
sets of 8 repetitions with
70% of 1RM)
MAPK
20 healthy but untrained

males
Heavy load increased phosphorylation of p70S6k, 4E-BP1,
Taylor
(2012)
High load (8-10 repetitions

with 80 85% of 1RM) vs.
moderate load (18-20
of 1RM)
MAPK

untrained males
Moderate led to a greater increase in IGF-1R and Elk-1 ac
Agergaard
(2013)

repetitions with 16% of
1RM) vs. heavy load (10
sets of 8 repetitions with
70% of 1RM)
Satellite
cells
20 healthy but untrained

males
Heavy led to greater mRNA expression of Myf6, Myogenin,
Gehlert
(2014)
Maximal eccentric vs. 75%

of stretch-shortening
cycle vs. 100% of stretchshortening cycle with
matched time-undertension
MAPK
and
mTOR
22 recreationally
resistance-trained young
males
Maximal eccentric displayed higher phosphorylation level

other two conditions
Popov
(2014)
Heavy (75% of 1RM) vs.

moderate (50% of 1RM)
for 8 sets of 12
repetitions, equalized for
time under tension
MAPK
and
mTOR
10 amateur athletes (sprint

and middle distance
runners)
Moderate displayed phosphorylation of p70S6K but heavy
No difference in phosphorylation of p70s6K and 4EBP1 at
Muscle protein synthesis

There are some indications that heavier relative loads may lead to
greater muscle protein synthesis than lighter relative loads.
The following table sets out studies that have compared muscle protein
synthesis between conditions with different relative loads.
Study
Comparison
Outcome
Population
Finding
Kumar
(2009
)
High load (6 sets of 3 repetitions

with 90% of 1 RM), vs. moderate
load (3 sets of 8 9 repetitions
Muscle
protein
synthesis
Two groups (25 each) of healthy, young (24 6

years) and old (70 5 years) males
No difference in muscle
subjects
Study
Comparison
Outcome
Population
Finding
Muscle
protein
synthesis
20 healthy but untrained males
Heavy load increased mu
with 6075% of 1RM)

Holm
(2010
)

repetitions with 16% of 1RM)
vs. heavy load (10 sets of 8
repetitions with 70% of 1RM)
PROBLEMS
Controlling other variables
Where maximal bar speeds are used, the force-velocity relationship is a

confounding factor when comparing groups training with different relative loads.
This is because the group training with the heavier relative load must use a
slower bar speed and consequently performs each repetition with a longer
repetition duration and (depending on whether volume is measured as sets x
repetitions or sets x repetitions x relative load) potentially also a longer total time
under tension for the workout.
However, when comparing two groups training with different relative loads in
which sub-maximal bar speeds are used, the force-velocity relationship does not
cause a problem. This is because the same bar speed can be used in both cases
(or a different bar speed in order to maintain total time under tension across the
workout by manipulating repetition duration).
Volume can be a confounding factor where individuals perform very different
numbers of repetitions with the same percentage of 1RM. Thus, where different
training groups are being compared that are performing programs using different
relative loads, some individuals might perform a greater volume of work than
others. While it is noted that several investigations have reported some variation
in respect of the number of repetitions that can be performed with a given
percentage of 1RM (Hoeger, 1987; Hoeger, 1990; Shimano, 2006; and Moraes,
2014), there does appear to be some degree of reliability in the extent to which
prediction equations can be used (Desgorces, 2010). Moreover, the effect of
exercise selection seems to be far more important for predicting the number of
repetitions that can be performed with a given percentage of 1RM than the exact
nature of the population (Hoeger, 1987; Hoeger, 1990; Shimano, 2006; Moraes,
2014; and Desgorces, 2010).
-
SELECTION CRITERIA
For the following analyses, studies were selected where: they compared
>2 resistance-training programs, where >2 groups trained with different relative
loads and at least one group used loads considered to be light, as defined as
<50% of 1RM, and at least one group used loads considered to be heavy, as
defined as >50% of 1RM. Outcome measures were rejected where muscular
hypertrophy was measured using arm or thigh circumference as these were
considered to be too easily affected by alterations in fat mass.
-
EFFECT OF RELATIVE LOAD ON HYPERTROPHY

(UNTRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Heavy significantly
better?
Weiss
(2000
)
Muscle thickness
using ultrasound
(quadriceps and
hamstrings)
44 untrained males,
aged 18 30 years
Heavy (3 5RM for 4 sets) vs. moderate (13

15RM for 4 sets) vs. light (23 25RM for 4 sets)
7 weeks
No differences betw
groups
Camp
os
(2002
)
Fiber CSA using

NIH imaging of
biopsies
32 untrained males,
aged 22.5 5.8
years

8 weeks
Heavy and moderate

superior to light
Tanim
oto
(2006
)
Muscular CSA
(thigh) using MRI
24 healthy but
untrained young
males aged 19 1
years
Light (50% of 1RM with 1s eccentric and

concentric) vs. heavy (80% of 1RM with 1s
concentric and eccentric)
12
weeks
Heavy superior to lig
Leger
(2006
)
Muscular
CSA using CT
scans
25 healthy but
untrained males,
aged 36 4.9 years

8 weeks
No differences betw
groups
Popov
(2006
)
Muscular
CSA using MRI
18 young, physically
active males, aged
21 2 years
Heavy (80% of MVC) vs. light (50% of MVC)
8 weeks
No differences betw
groups
Holm
(2008
)
Muscular
CSA using MRI
11 sedentary males,
aged 25 1 years
One leg with 70% of 1RM (heavy load) and

one leg with 15.5% of 1RM (light load)
12
weeks
Muscle thickness
using ultrasound
36 healthy but
untrained young
males aged 19 1
years
Light (55 60% of 1RM with 3s eccentric and

concentric) vs. heavy (80 90% of 1RM with 1s
concentric and eccentric)
13
weeks
No differences betw
groups
Tanim
oto
(2008
)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Heavy significantly
better?
Schue
nke
(2012
)
Fiber CSA
using NIH
imaging of
biopsies
34 untrained
females, aged 21.1
2.7 years
Heavy (6 10RM with 1-2s concentric and 1-2s

eccentric at 80 85% of 1RM) vs. light (20
30RM with 1-2s concentric and 1-2s eccentric
at 40 60% of 1RM)
6 weeks
Mitch
ell
(2012
)
Muscular volume
using MRI scans
18 healthy,
untrained young
males aged 21 0.8
years
30% of 1RM x 3 sets vs. 80% of 1RM x 1 set vs.

80% of 1RM x 3 sets
10
weeks
No differences betw
groups
Ogasa
wara
(2013
)
Muscular
CSA using MRI
scans
9 young, untrained
males aged 25 3
years
Heavy (75% of 1RM for 3 sets) vs. light (30% of

1RM for 4 sets)
6 weeks
No differences betw
groups
12
weeks
No differences betw
groups
16
weeks
No differences betw
groups
Van
Roie
(2013
)
Muscle volume
using CT scans
56 adults aged >60

years
Heavy (2 1015 reps at 80% of 1RM) vs. light (1

80100 reps at 20% of 1RM) vs. light+ (1 60
reps at 20% of 1RM, followed by 1 1020 reps
at 40% of 1RM)
Reid
(2014
)
Muscular
CSA using CT
scans
52 elderly subjects
(78 5 years)
Heavy (3 sets of 10 reps at 70% of 1RM) vs. light

(3 sets of 10 reps at 40% of 1RM)

In untrained individuals, high relative loads (<15RM) might be superior to a low
relative loads (>15RM) for hypertrophy but the research is slightly conflicting. There is
no evidence available to ascertain the effect of relative load in trained individuals.
VOLUME
PURPOSE
This section explores whether training with a higher volume is more
effective than training with a lower volume for hypertrophy. This is
achieved by looking at long-term studies that compare different volumes
of training for increasing muscular mass or size.
BACKGROUND
Definitions
For the purposes of analyzing volume as a training variable in its own right,
volume can be very simply defined as the number of sets of an exercise. Thus, in
the vast majority of studies investigating the effect of training volume on
hypertrophy multiple sets of an exercise are compared with single sets. In a small
minority, a larger number of sets of a fixed number of repetitions are compared
with a smaller number of sets of the same number of repetitions.
For controlling volume when analyzing the effects of other training variables (such
as relative load, proximity to muscular failure, range of motion, rest period
duration, bar speed, muscle action, or periodization type), at least three methods
of equating volume between conditions are possible. Firstly and most easily,
volume can be defined as the number of sets x the number of repetitions.
However, this is problematic when comparing the effects of training variables that
involve different absolute or relative loads, as either the total amount of weight
lifted differs or the proximity to muscular failure differs or both. Consequently,
other methods of equating volume have been developed. One method involves
equating the mechanical work performed by reference to the load lifted (number
of sets x the number of repetitions x the absolute load). This has been termed the
volume load (Stone et al. 1998). However, where different muscle actions, submaximal bar speeds, or relative loads are compared this will likely lead to
differences in proximity to muscular failure between conditions.
Popular usage
Many professional bodybuilders currently train with very high volumes to
maximize hypertrophy, although the role of anabolic androgenic steroids (AAS) in
helping them recover from this heavy workload is unclear. Despite the huge
success of this majority, a vocal minority of personal trainers and researchers still
maintain that high-intensity, low-volume training (HIT) is superior.
Literature usage
Researchers have studied the effect of volume on hypertrophy more than any
other single training variable. This relatively extensive body of literature (in
comparison with other training variables) has led to the production of many
reviews and one or two meta-analyses.
META-ANALYSES
Findings
Krieger (2010) performed a meta-analysis to assess the effect of volume on
hypertrophy. Krieger (2010) observed that multiple sets are associated with 40%
greater hypertrophy-related effect sizes than single sets, in both trained and
untrained subjects.
Challenges
There are two significant challenges associated with studying the effect of any
training variable on hypertrophy that are useful to consider before interpreting
the findings of a meta-analysis. In respect of the meta-analysis performed by
Krieger (2010), the main challenges have been outlined in an extensive analysis
by Fisher (2012). The main issues raised in this commentary are set out below.
Firstly, it is problematic that the magnitude of hypertrophy following a resistance
training program is generally much smaller than the gains in strength. Since
effect sizes are usually calculated as the mean divided by the standard deviation,
the small magnitude of the mean increase means that the effect sizes that are
reported following a resistance training intervention tend to be quite small. When
comparing one resistance training intervention comprising a high volume with
another comprising a lower volume, the effect sizes are even smaller. Thus, when
considering a meta-analysis of effect sizes to assess the overall effect of a
training variable on hypertrophy, it is likely that many of the individual studies will
report no overall significant effect while the meta-analysis could report an overall
effect because of the type II error occurring within each study.
Secondly, a related issue is that many studies exploring the effects of different
resistance training programs tend to display a great deal of variability between
subjects (e.g. Hubal et al. 2005; Bamman et al. 2007; review by Timmons, 2011).
This large variability increases the magnitude of the standard deviation
considerably. Since effect sizes are usually calculated as the mean divided by the
standard deviation, this further reduces the effect sizes that are reported
following a resistance training intervention. Thus, when considering a meta-
analysis of effect sizes to assess the overall effect of a training variable on

hypertrophy, it is likely that many of the individual studies will report no overall
significant effect while the meta-analysis could report an overall effect because of
the type II error occurring within each study.
To counter these two issues, it is important to use studies that are designed to
bring about large increases in muscle mass with comparatively low interindividual variability or at least sufficient statistical power to counter the effects of
such variability. The main tools that researchers have to achieve this are long
study durations and large sample sizes. Unfortunately, owing to funding
constraints, most trials studying hypertrophy tend to involve relatively few
subjects over short durations. Other methods for reducing the inter-individual
variability that researchers have only recently begun to investigate include the
use of a pre-intervention intervention, in which responders and non-responders
are identified. However, this method of identifying and reducing inter-individual
variability has not yet been implemented in the comparison of training variables.
-

VOLUME

The main stimulus for hypertrophy is thought to be the application of mechanical
loading. Greater stimulus is thought to arise from more prolonged periods in
which the muscle is subjected to this mechanical load. Hence, a greater volume of
training might be assumed to be more effective than a smaller volume of training,
as it involves a longer duration of time during which the muscle is exposed to the
stimulus.
Nevertheless, it is almost certain that no linear relationship between volume and
hypertrophic stimulus exists but rather than a plateau occurs after a certain
point has been reached, within the boundaries of a certain time course. This can
be deduced from a number of animal trials that have exposed rodent subjects to
excessive training volume with insufficient recovery and found that this leads to
muscular atrophy (Souza et al. 2011; Souza et al. 2014). On this basis, it
is assumed that there is a specific training volume over a specific certain period
of time that leads to maximum hypertrophy and increasing the volume further will
not lead to bigger increases in muscular size and may in fact lead to decreases in
muscular size if the volume becomes excessive.
In summary, a higher volume might be effective than a lower volume for
hypertrophy on the basis that the tensile force in the muscle is longer in
duration, subject to adequate recovery being possible. Whether this
volume needs to be greater only than a certain threshold or whether
there is a dose-response effect is unclear.
-

There are some indications that a greater training volume appears to
lead to greater molecular signalling responses than a smaller training
volume.
responses between conditions with different volumes.
Study
Comparison
Pathway
Population
Finding
Wilbor
n
(2009
)
High-load-low volume (80 85% of 1RM) vs.

moderate-load-high-volume (60 65% of
1RM)
Satellite
cells
13 recreationally active but untrained

males
No difference between condit

myogenin, MRF-4 and myf5) an
Terzis
(2010
)
Low (1 set) vs. moderate (3 sets) vs. high (5

sets) volumes
mTOR

males
Higher volume led to increase

phosphorylation between cond
Burd
(2010
)
Low (1 set) vs. moderate (3 sets) volumes
mTOR
8 resistance-trained males
Higher volume involved greate
Taylor
(2012
)

1RM)
mTOR

males
Higher volume displayed a gre

MAPK and ERK1/2 between co
Hulmi
(2012
)

1RM)
mTOR
and
MAPK

males
Higher volume led to greater p
Kumar
(2012
4 workout protocols: low or high relative

loads (40% or 75% of 1RM) with low or high
mTOR
12 young and 12 older males
Higher volume led to greater p
Study
Comparison
volumes (3 or 6 sets)
Pathway
Population
Finding

There are some indications that a greater training volume appears to
lead to a greater acute muscle protein synthesis than a smaller training
volume.
The following table sets out studies that have compared acute muscle protein
synthesis between conditions with different volumes.
Study
Comparison
Pathway
Population
Finding
Burd
(2010
)
Low (1 set) vs. moderate (3 sets) volumes
mTOR
8 resistance-trained
males
Higher volume involved greater increases in
PROBLEMS
When studying the effect of any individual training variable on hypertrophy, a
major problem is the extent to which other training variables can be fixed
between the two groups being compared. The most important training variables
to fix are those that have been found to have the biggest effect on hypertrophy. In
the case of volume, there are few other training variables that have been found to
have as significant an effect. However, since volume can be increased by simply
adding extra sets onto a workout, it is relatively easy to control for other potential
confounding factors, such as proximity to muscular failure, frequency, and relative
load.
SELECTION CRITERIA
>2 resistance-training programs, where >2 groups trained with different volumes,
largely as a result of performing a different number of sets in what was otherwise
an identical workout.
EFFECT OF VOLUME ON
HYPERTROPHY (TRAINED)
Study
Outcome
measure for
hypertroph
y
Ostrowsk
i (1997)
Rhea
(2002)
Population
Comparisons
Muscular
CSA using
ultrasound
(rectus
femoris and
triceps
brachii)
27 males with
>1 year weighttraining
experience
Low (3 sets per

week) vs.
moderate (6 sets
per week) vs.
high (12 sets per
week)
Lean body
mass using
Bod Pod
18
recreationally
trained young
males with >2
years weighttraining
experience
Low (1 set) vs.

high (3 sets)
Higher
volume
significantl
y better?
Absolute
differences
10
weeks
No
difference
between
groups
Rectus
femoris/triceps
brachii: high =
13.1%/4.8%,
moderate =
5.0%/4.7%, low =
6.8%/2.3%
12
weeks
No
difference
between
groups
Low = 0.9 0.7%

and high = 1.3
0.6%
Duration
EFFECT OF VOLUME ON
HYPERTROPHY (UNTRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Durati
on
Higher volume significantly better?
Absolute diffe
Galvo
(2005)
Bone-mineralfree lean body

mass using
DEXA
28 communitydwelling men and

women, aged 65
78 years
Low (1 set)
vs. high (3
sets)
20
weeks
No difference between groups
Low = 0.5kg an
Marzolini
(2008)
Lean body mass

measured by
DEXA (total,
trunk, arms,
legs)
53 patients with
coronary artery
disease, aged 61
2 years
Low (1 set)
vs. high (3
sets)
24
weeks
Total, trunk, arm lean body mass: no

differences between groups. Leg lean
body mass: high superior to low
Total lean bod
McBride
(2003)
Lean body mass

measured by
DEXA (arms and
legs)
28 untrained
males and
females, aged ~
20 22 years
Low (1 set)
vs. high (6
sets)
12
weeks
Arms/legs: low
Low (1 set)
vs. high (3
sets), either
fast or slow
6
weeks
Fast/slow: low
Munn
(2005)
Arm
circumference
115 untrained
males and
females,
aged 20.6 6.1
years
Rnnest
ad
(2007)
Muscular CSA
using MRI (thigh
and trapezius)
21 untrained
males, aged 27
2 years
Low (1 set)
vs. high (3
sets)
11
weeks
Thigh muscle CSA: high superior to

low; trapezius: no differences
between groups
Thigh: high = 1
Muscle thickness
using ultrasound
(thigh muscles)
10 healthy but
untrained
subjects, aged 18
50 years
Low (1 set)
vs. high (3
sets)
14
weeks
Anterior and lateral thigh: no

difference between groups; medial
thigh: high greater than low
Medial: high =
Starkey
(1996)
Outcome
measure for
hypertrophy
Population
Comparisons
Durati
on
Higher volume significantly better?
Absolute diffe
Bottaro
(2011)
Muscle thickness
using ultrasound
(rectus femoris
and biceps
brachii)
30 young males,
aged ~ 20 22
years
Low (1 set)
vs. high (3
sets)
12
weeks
Biceps brachii
Sooneste
(2013)
Muscular CSA
using MRI (elbow
flexors)
8 sedentary
young males,
aged 25.0 2.1
years
Low (1 set)
vs. high (3
sets)
12
weeks
High greater than low
High = 13.3 3
Radaelli
(2013)
Muscle thickness
using ultrasound
(quadriceps and
elbow flexors)
20 healthy, older
women, aged 60
74 years
Low (1 set)
vs. high (3
sets)
13
weeks
Quadriceps/el
2.0%/11.2 6.
Correa
(2014)
Muscle volume
using ultrasound
(rectus femoris)
35 healthy
postmenopausal
women, aged
59.5 6.3 years
Low (1 set)
vs. high (3
sets)
12
weeks
Exact numbers
Study

For untrained individuals, several studies show that multiple sets leading to greater
total volume appear to cause greater hypertrophy.
For trained individuals, there is much less evidence but multiple sets leading greater
total volume also appears to be superior to single sets.

-
MUSCULAR FAILURE
PURPOSE
This section explores whether training to muscular failure, or with closer
proximity to fatigue, is superior for hypertrophy. This is achieved by
looking at long-term studies that compare whether a program where
subjects train to muscular failure is better than a program where
subjects do not train to muscular failure for increasing muscular mass or
size.
BACKGROUND
Definitions
Muscular failure is a term frequently used in research studies investigating
resistance training programs but precise definitions of this term are infrequently
discussed. Willardson (2007) defined muscular failure as the point during a
resistance exercise set when the muscles can no longer produce sufficient force to
control a given load. Schoenfeld (2010) tightened this definition by stating
that muscular failure involved the point during a set when muscles can no longer
produce necessary force to concentrically lift a given load. This definition
therefore necessitates the use of concentric muscle actions. In their review, Fisher
et al. (2011) tightened the definition even further by defining muscular failure as
the inability to perform any more concentric contractions, without significant
change to posture or repetition duration, against a given resistance.
Whether such additions are necessary to the original definition provided by
Willardson (2007) is probably a moot point. The important factor of the definition
is that muscular failure can only be defined in relation to a given load. This should
be immediately apparent when bodybuilders are observed performing repetitions
to failure and then immediately dropping the weight and using a lighter weight to
continue performing several more repetitions. Thus, muscular failure does not
mean that a muscle is incapable of performing further muscle actions and
therefore we cannot say that muscular failure is equivalent to being maximally
fatigued (Willardson, 2007). Muscular failure means that a muscle is incapable of
expressing force at the same level as it was able to previously, such that it is no
longer able to move an arbitrary weight that was set for the task at hand.
Popular usage
Muscular failure is often used by individuals in the general population who
perform resistance training for reasons relating to health or physical appearance.
Additionally, many strength athletes also regularly train to failure,
especially bodybuilders. Some powerlifting groups also train to muscular failure,
especially in low repetition ranges. However, not training to muscular failure is
also very common.
Literature usage
In the research literature, it is extremely common for all sets of an exercise to be

prescribed to muscular failure. In fact, it is quite rare that a study into
hypertrophy is performed where muscular failure is not reached on all sets of
each exercise. This seems to be because it is considered beneficial to ensure that
all sets of an exercise are matched between individuals in terms of their fatigue
levels at that time. Thus, it is important to note that there is a slight discrepancy
between the research literature and general practice. The study of whether
muscular failure is important for hypertrophy is therefore critical.
-
MECHANISMS FOR HYPERTROPHY IN RELATION

TO MUSCULAR FAILURE

THE SIZE PRINCIPLE AND MOTOR UNIT RECRUITMENT
loading. Mechanical loading can be applied both actively (through neural activity
leading to motor unit recruitment and contractile activity) or passively (through
passive stretch). Active muscle actions involve a neural signal that activates
motor units in the muscle, which each recruit a group of dedicated muscle
fibers. Hennemans size principle (see reviews by Enoka, 1984; Heckman and
Enoka, 2012; Bawa et al. 2014) states that smaller and weaker motor units
(innervating few muscle fibers) are recruited before larger and stronger motor
units (innervating larger numbers of muscle fibers). Thus, muscular activation
proceeds progressively from small to large motor units with increasing magnitude
of the neural signal. The greater the neural signal, the more motor units are
activated and consequently the more muscle fibers are recruited. The more
sustained the neural signal, the longer the motor units remain activated and the
longer the muscle fibers remain recruited, thereby producing force for a longer
period of time. It is thought that the recruitment of the motor units is necessary
for the subsequent hypertrophy of the associated muscle fibers.
MUSCULAR FAILURE AND MOTOR UNIT RECRUITMENT
Until recently, muscular failure has been assumed by many researchers to imply
automatically that full motor unit recruitment also occurs (Burd et al. 2012a; Van
Roie et al. 2013). Indeed, this assumption led to the theory being developed that
low load training to muscular failure was as effective as high relative load training
(Burd et al. 2012a), which is indeed a logical consequence. The theory has
been debated at some length (Burd et al. 2013; Schuenke et al. 2013) although
this debate has occurred largely in the absence of investigations that have
directly explored whether muscular failure does in fact lead to full motor unit
recruitment. This is surprising, as the issue was in fact raised many years
previously (Stone et al. 1996).
ASSESSING MOTOR UNIT RECRUITMENT USING EMG
Some recent studies have used electromyography (EMG) to assess
whether muscular failure is synonymous with full motor unit recruitment. Recent
findings in fact suggest that relative load may be as important if not more
important. Sundstrup et al. (2012) explored the EMG activity of the shoulder and
neck muscles during lateral raises performed with low relative loads (15RM) to
muscular failure and with high relative loads (3RM) not to muscular
failure. Sundstrup et al. (2012) found that a plateau in muscle activity was
reached at 10 12 reps of the 15RM load, which they interpreted to mean that
training to complete failure is not necessary to fully recruit the entire motor unit
pool, at least in untrained individuals.
Additionally, several other researchers have compared the EMG activity with high
and low relative loads, using the leg press (Schoenfeld et al. 2014), knee
extension without blood flow restriction (Akima and Saito, 2013) and knee
extension with blood flow restriction (BFR) (Cook et al. 2013). All of these studies
have reported that high relative loads lead to greater EMG activity in the working
muscle than low relative loads when repetitions are performed to muscular
failure. Whether the addition of BFR has any effect is unclear, as Wernbom et al.
(2009) reported no differences in EMG activity between low relative loads

performed to muscular failure with and without BFR. These findings suggest that
the theory of muscular failure being completely synonymous with motor unit
recruitment may not correct. On the other hand, the studies all show that
approaching muscular failure does lead to increased EMG activity, indicating that
it may still be beneficial for increasing motor unit recruitment and ultimately
therefore probably also hypertrophy.
LIMITATIONS OF USING EMG TO ASSESS MOTOR UNIT RECRUITMENT
There are many limitations associated with using EMG to assess the extent of
motor unit recruitment. Most importantly, the magnitude of the EMG
output reported (typically normalized to the level observed during maximum
voluntary isometric contractions) does not differentiate between the component
elements of the neural signal. Consequently, the magnitude of the signal can
depend upon a range of factors, including neural ones (the number of motor units
recruited and the level of rate coding) and peripheral ones (the speed of
the muscle fiber propagation velocity and the strength of the intracellular action
potentials).
Therefore, while it is thought that EMG as measured using surface electrodes can
provide an indication of the number of motor units that are active at any one
time, it does not allow us to determine the exact number because it measures a
multitude of different factors within the overall strength of the EMG signal. Thus, a
comparison of the number of recruited motor units between trials is difficult.
Additionally, it is thought that, during very fatiguing contractions, some heavily
fatigued motor units are de-recruited, if only temporarily, which then allows a
reduction in fatigue. Thus, at any given point in time within a fatiguing
contraction, there may be a different combination of motor units that are
recruited for generating the same level of force production. This adds an
additional level of complexity.
In summary, training closer to muscular failure might be more effective
than training further from muscular failure for hypertrophy on the basis
that a greater neural signal occurs and consequently more motor units
are recruited with closer proximity to muscular failure.
-

There are some indications that molecular signalling responses might be
increased as a result of training closer to muscular failure.
responses for hypertrophy between conditions performed closer to or further from
muscular failure.
Study
Comparison
Pathway
Population
Finding
Burd
(2010
a)
Muscular failure with 90% of 1RM (90F),

muscular failure with 30% of 1RM
(30F), and 30% of 1RM (30WM) workmatched to the 90% of 1RM condition
mTOR
and MAPK
15 recreationally active
but untrained males
Phosphorylation of Erk1/2, p70S6k, and 4E-BP

two conditions
Burd
(2012
)
Muscle actions comprising 3 sets

with 30% of 1RM in either slow (6second) to failure or workmatched fast but not to failure (1second) conditions
mTOR
8 recreationally
resistance-trained males
Failure increased phosphorylation of p70S6K w

There are some indications that muscular failure may be important for
maximizing muscle protein synthesis post-workout, although the
literature is very limited at present.
Stud
y
Burd
(2012
)
Comparison
Muscle actions comprising 3 sets with 30% of 1RM in either
slow (6-second) to failure or work-matched fast but not to
failure (1-second) conditions
Outcome
Muscle protein
synthesis
Population
8 recreationally
resistance-trained males
PROBLEMS
Finding
Failure increased mus
to fix are those that have been found to have the biggest effect on hypertrophy
(i.e. volume). In the case of muscular failure, it is relatively easy to control for the
effect of volume while varying whether individuals train to muscular failure by
simply inserting an intra-set rest period.
Ecological validity
In the research literature exploring the effect of muscular failure on hypertrophy,
it is most common for the effect of muscular failure to be assessed by comparing
two groups, one that uses an intra-set rest period and that does not. However, in
practice, this is not how individuals who do not train to muscular failure actually
perform resistance-training. Such individuals generally stop slightly short of
muscular failure, leaving a repetition or two in the tank. Given the observations
made above, this could be important. There is therefore a discrepancy between
the research literature and general practice, indicating a lack of ecological
validity.
SELECTION CRITERIA
>2 resistance-training programs, where either 1 of the groups trained either to
muscular failure and the other group did not, where 1 of the groups trained to a
closer proximity to fatigue than the other group. Studies were sought that used
the same exercises and used equal or near equal training volumes. Outcome
measures were rejected where muscular hypertrophy was measured using arm or
thigh circumference as these were considered to be too easily affected by
alterations in fat mass.
-
EFFECT OF MUSCULAR FAILURE ON

Stud
y
Outcome measure for

hypertrophy
Population
Comparisons
Durati
on
Closer to failure significantly better?
Goto
(200
Muscular CSA using

MRI scans (quadriceps)
26 healthy
male
10RM with or without a 30second intra-set rest
12
weeks
Group closer to failure increased more than group

further from failure
Stud
y
Outcome measure for

hypertrophy
Population
Comparisons
5)
subjects
period
Scho
tt
(199
5)
7 healthy
subjects,
training
right and
left legs
Long, continuous isometric

contractions (30 seconds)
vs. equal volume of short,
intermittent isometric
contractions (3 seconds)
Muscular CSA using CT

scans (upper and
lower femur)
Durati
on
Closer to failure significantly better?
14
weeks
Group closer to failure increased more than group

further from failure

For untrained individuals, training closer to muscular failure appears to lead to greater
hypertrophy.
For trained individuals, there is unfortunately currently no available evidence.

-
FREQUENCY
PURPOSE
This section explores whether training with a higher volume-matched
frequency (i.e. number of training sessions per week) is more effective
for hypertrophy than training with a lower volume-matched frequency.
This is achieved by looking at long-term studies that compare whether a
program where subjects train with different training frequencies and
assessing their relative ability for increasing muscular mass or size.
BACKGROUND
Definitions
Training frequency is most commonly defined as the number of times per week
that resistance training is performed, whether in relation to the whole body or a
single muscle.
Popular usage
Training frequency is often a topic of discussion in the bodybuilding community

where interested parties want to know how many times per week they should
train a particular muscle. In general, such questions generally assume that the
total training volume over the week is fixed because of the need for recovery.
Thus, the question becomes how the training volume is best distributed over the
course of the week.
More widely, people embarking upon a program of resistance training often wish
to know whether they should follow a whole-body or a split routine. Whole-body
routines involve training both the upper and lower body in the same workout and
workouts are typically performed 3 times per week, with the other days being
devoted to rest. Simple split routines for beginners are formed by training the
upper and lower body on separate days, most commonly by training 4 times per
week, with the other days being devoted to rest. More complex split routines are
performed by more advanced trainees and these can involve 5 or 6 days per
week of training.
-

FREQUENCY

load to a joint, which results in tensile force within the muscle. Greater stimulus is
thought to arise from more prolonged periods in which the muscle is subjected to
this mechanical load. Within certain boundaries, training volume is closely tied to
the resulting hypertrophic stimulus. However, there are good grounds for
believing that there is a finite limit to both the volume that can be performed in a
single workout (and over multiple sequential workouts) and the resulting
hypertrophic stimulus, because of the need for adequate recovery. Thus, an
optimal structure of volume-matched training frequency must exist, whereby

individual workouts create the greatest possible stimulus.
In summary, training with a specific volume-matched frequency might
be more effective than another volume-matched frequency because the
distribution of the hypertrophic stimuli over the course of a training
week are optimal in one case and not in the other. The extent to which
the pattern of this distribution varies between individuals is unclear and
may affect our ability to test this training variable accurately.
PROBLEMS
Controlling other variables when studying volume-matched training frequency is
in theory relatively straightforward. A certain volume of training is identified and
then allocated across two workout plans. The workout plan for one group involves
a greater workload in a single workout than the other but performs fewer
workouts over the course of the week. In practice, when working with trained
subjects, it is slightly more complicated, as the only practical way to increase
volume-matched training frequency is to train multiple times on the same day,
which introduces a time-of-day effect. Training at different times of day has been
found by some (Chtourou and Souissi, 2012) but not all (Sedliak et al. 2009) to
affect muscular adaptations to training and may therefore be a confounding
factor.
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained with a lower
volume-matched frequency than the other. Studies were sought that used the
same exercises in both groups.
-
EFFECT OF FREQUENCY ON HYPERTROPHY

(TRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Highe
bette
McLester
(2000)
Lean body
mass
estimated
using skin-fold
callipers
25 recreationally resistancetrained males and females
Low (1 day per week for 3 sets) vs. high (3 days per
week for 1 set)
12
weeks
No dif
Hkkinen an
d Kallinen
(1994)
Muscular CSA
(quadriceps)
using
ultrasound
10 females with >2 years of

resistance-training
experience
Low (once per day, 3.5 days per week) vs. high
(twice per day, 3.5 days per week)
6 weeks
High i
Hartmann
(2007)
Muscular CSA
(rectus
femoris) using
ultrasound
10 nationally competitive
male Olympic weightlifters
Low (once per day, 4 days per week) vs. high (twice
per day, 4 days per week)
3 weeks
No dif
EFFECT OF FREQUENCY ON HYPERTROPHY

(UNTRAINED)
Study
Outcome measure for

hypertrophy
Population
Comparisons
Duration
Higher fr
better?
Calder
(1994)
Lean body mass (trunk,

leg, total) using DEXA
scans
30 young female
subjects, aged ~ 20
22 years
Low (2 times per week) vs. high (4 times per

week)
10
weeks
Trunk and
between
but high
Benton
(2011)
Lean body mass using

Bod Pod
23 untrained females,
aged 40 55 years
Moderate (3 days per week) vs. high (4 days

per week)
8 weeks
No differ
Lean body mass (total)

using DEXA
29 untrained males
and females, aged 27
58 years
Moderate (3 sets, 2 days per week) vs. high

(2 sets, 3 days per week)
6 weeks
No differ
Arm and thigh

circumferences
39 healthy but
untrained males,
aged ~ 20 years
Low whole-body (12 exercises, 1 time a

week), whole-body (6 exercises, 2 times a
week), and upper-lower split (4 exercises,
3 times a week)
8 weeks
No differ
Candow and
Burke
(2007)
Arazi and
Asadi
(2011)

For untrained individuals, altering volume-matched
training frequency does not seem to have any effect on
hypertrophy.
For trained individuals, a higher volume-matched training

frequency seems to be superior to a lower frequency for
hypertrophy.
-
REST PERIODS
PURPOSE
This section explores whether training with shorter inter-set rest
periods is superior to training with longer inter-set rest periods for
hypertrophy. This is achieved by looking at long-term studies that
compare whether a program where subjects train with short inter-set
rest periods (or reducing rest periods) is better than a program where
subjects train with longer inter-set rest periods (or with non-reducing
rest periods) for increasing muscular mass or size.
BACKGROUND
Definitions
Resistance training exercises are generally described as being performed in sets
of repetitions, where a set is a number of repetitions performed in sequence.
Where multiple sets of repetitions are performed, there is a rest between sets,
called the inter-set rest period. The length of this inter-set rest period can be
referred to as the inter-set rest period duration.
Popular usage
Many bodybuilders believe that training with shorter inter-set rest period
durations leads to superior gains in muscular size. Popular bodybuilding
magazines and experts both proclaim the use of shorter inter-set rest period
durations for maximizing hypertrophy.
Literature usage
Unfortunately, researchers have not performed very many trials in order to
measure the effects of altering inter-set rest period duration on hypertrophy.
Some researchers and coaches have attempted to rely upon the use of acute
trials in order to provide evidence-based guidelines for inter-set rest period
duration, suggesting that because short rest periods lead to increased metabolic
stress, they must lead to superior gains in muscular size. However, this ignores
the smaller stimulus that likely ensues from performing fewer total repetitions or
using a lighter relative load and therefore lower mechanical tension.
-

REST PERIODS

loading to a joint, which results in tensile force within the muscle. Greater
stimulus is thought to arise from more prolonged periods in which the muscle is
subjected to this mechanical loading. Within certain boundaries, training volume
is closely tied to the resulting hypertrophic stimulus. However, performing
consecutive sets with the same relative load but shorter rest periods leads to
fewer repetitions being performed than when longer rest periods are used
(Miranda et al. 2009; Senna et al. 2009; Senna et al. 2011). Thus, unless
additional sets are performed in order to match volumes, it is likely that using
shorter rest periods will reduce volume and consequently reduce the stimulus
provided by the mechanical load.

stress (see reviews by Schoenfeld, 2010; Schoenfeld, 2013; Pearson and Hussain,
2014). There is a clear mechanism by which shorter rest periods could lead to
increased metabolic stress, as muscular contractions above a certain (fairly low)
threshold of maximum voluntary isometric contraction force prevent venous
return. Since metabolic stress arises from the prevention of venous return, cell
swelling and the buildup of metabolites such as blood lactate, intramuscular
lactate, glucose and glucose-6-phosphate within the muscle in concert with the
experience of a muscle pump (see review by Schoenfeld and Contreras, 2014),
shorter rest periods would be expected to lead to greater metabolic stress and
consequently greater hypertrophy, so long as all other factors remained constant.
Previously, it was thought that a key factor in determining the extent to which
hypertrophy occurred following a program of resistance training was the acute
post-workout hormone response to training, which apparently results from greater
metabolic stress (see reviews by Schoenfeld, 2013a; Henselmans and Schoenfeld,
2014). This idea has been termed the hormone hypothesis and has since been
rejected by many researchers. It has been concluded that it is impossible to
conclude on whether post-workout hormone responses have any effect on longterm hypertrophy but nevertheless suggested that any effect would likely
be small in any event (see reviews by Schoenfeld, 2013a; Henselmans and
Schoenfeld, 2014).
In summary, training with shorter rest periods could either be more or
less effective than with longer rest periods, depending on whether
the stimulus from the mechanical load or the metabolic stress is greater,
and on whether the short-rest and long-rest programs are volumematched.
-

The majority of studies comparing the acute responses of different rest
period durations have done so in respect of hormone levels rather than
molecules within the key pathways.
responses for hypertrophy between conditions performed with long or short rest
periods.
Study
Comparison
Pathway
Population
Finding
Boroujerdi
and Rahimi
(2008)
Short (1 minute) vs.

long (3 minutes) rest
periods
mTOR
10 recreationally resistancetrained males
Changes in serum growth hormone (GH) and blood lac

but there was no difference in respect of IGF-1.
Rahimi
(2010)
Short (60 seconds) vs.

moderate (90 seconds)
vs. long (120 seconds)
rest periods
mTOR
10 recreationally resistancetrained males
Changes in blood lactate and serum IGF-1 concentrati
PROBLEMS
The main problem associated with altering rest period duration is controlling
volume. As noted above, when reducing rest period duration, this leads to a
reduction in the number of repetitions that can be performed in a single set. Thus,
in order to control for volume while altering rest period duration while maintaining
all sets to muscular failure, an additional set would be required in the condition
with the shorter rest period duration.
-
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained with shorter interset rest period duration than the other group. Studies were sought that used the
same exercises and used equal or near equal training volumes.
-
EFFECTS OF REST PERIOD DURATION ON

Study
Outcome measure
for hypertrophy
Population
Comparisons
Duration
Ahtiainen
(2005)
Muscular CSA
(quadriceps) using
MRI scans
13 recreationally resistance-trained male

subjects, aged 28.7 6.2 years
Short rest (2 minutes) vs. long

rest (5 minutes)
6
months
EFFECTS OF REDUCING REST PERIOD DURATION

ON HYPERTROPHY (TRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Shorter rest periods

significantly better?
De
SouzaJunior
(2010)
Muscular CSA (arm

and thigh) using
MRI scans
20 recreationallytrained males
Constant rest (2 minutes) vs.

decreasing rest (2 minutes -> 30
seconds)
6 weeks
No significant
differences
EFFECTS OF REST PERIOD DURATION ON

Study
Outcome measure for

hypertrophy
Population
Comparisons
Durati
on
Shorter rest per
Buresh
(2009)
Muscular CSA (arms and

legs) estimated from
hydrostatic weighing
12 untrained males
Short rest (1 minute) vs. long rest (2.5

minutes)
10
weeks
Longer rest peri

difference for le
Villanue
va
(2014)
Lean body mass using

DEXA scans
22 elderly,
untrained males, aged 68
4.1 years
Short rest (1 minute) vs. long rest (4

minutes)
12
weeks
Shorter rest per

For untrained individuals, there is very limited evidence
but longer rest periods may be better for hypertrophy.
For trained individuals, rest period duration seems to
make little difference.
-
RANGE OF MOTION
PURPOSE
This section explores whether training through larger ranges of motion

(ROMs) leads to greater hypertrophy than training through smaller
ROMs. This is achieved by looking at long-term studies that compare
whether a program where subjects train through large ROMs is better
than a program where subjects train through small ROMs for increasing
muscular mass or size.
BACKGROUND
Definitions
Resistance training exercises are often described as being performed
either through full ROMs or partial ROMs. For single-joint exercises, full ROMs can
be defined as those in which the joint moves through its entire movement arc,
subject to the constraints of passive tissues. Thus, full joint ROM is broadly
equivalent to the muscle fully elongating. On the other hand, for multi-joint
exercises, full ROMs are more difficult to define, as not all of the joints will
necessarily move through their full movement arcs. For example, in a full ROM
squat, the ankle joint does not move through its full ROM. Similarly, in a full ROM
deadlift, the knee does not move through its full ROM. In the case of the deadlift,
greater ROM than full ROM can be achieved by using a snatch grip or by using a
platform to perform a deficit deadlift. Thus, for multi-joint exercises, full ROM may
need to be defined conventionally as greater ROM rather than full ROM.
Popular usage
Within wider strength and conditioning circles, there have been many
discussions around ROM in respect of squats, with some favouring deep squats
(and concomitantly lighter loads) and others favouring shallow squats (with much
greater loads). Other than for squats, however, ROM has never been a particularly
common topic of discussion. This is likely because there is no specific sensory
feeling associated with ROM. Unlike using shorter rest periods or training to
muscular failure, there is no sensation of great effort and burning fatigue within
the muscle, which lead the trainee to believe that they are stimulating growth.
Literature usage
Researchers have only recently begun to study whether ROM affects hypertrophy.
It is therefore not well-studied in comparison with other training variables, such as
volume or relative load.
-

RANGE OF MOTION

The most common stimulus for hypertrophy is thought to be mechanical loading,
which most often involves the development of tensile force in the muscles.
Traditionally, many strength coaches have assumed that using a partial ROM
might be superior to using a full ROM for increasing muscle mass because a
partial ROM typically allows greater absolute load to be lifted for the same relative
load in many common barbell exercises. The greater absolute load is assumed to
lead to greater tensile forces within the muscles. For the squat, this has been
observed both anecdotally but also in research, with greater net joint moments
being recorded at greater angles of knee flexion (Bryanton et al. 2012). Thus, it is
expected that greater absolute loads might be in turn lead to greater tensile force
experienced by the muscle. However, this ignores the fact that net joint moments
are the product of the barbell load and the external moment arm length.
Consequently, although the barbell load is greater in the partial ROM condition,
the external moment arm length is smaller. Thus, a smaller barbell load at
full ROM can involve a similar net joint moment to a larger barbell load at a partial
ROM.
When studying multi-joint movements, such as the squat, it is important to note
the phenomenon of relative muscular effort (Bryanton et al. 2012). This
phenomenon occurs is where the various prime movers contribute to a different
extent to the overall movement, depending on the relative load or ROM used. This
phenomenon has been observed in the squat in terms of net joint moments
(Beardsley and Contreras, 2014), EMG activity, and musculoskeletal modelling
forces (Beardsley and Contreras, 2014a). Thus, using different ROMs in the squat
might reasonably be expected to produce different degrees of hypertrophy in the
prime movers (quadriceps, gluteus maximus and hamstrings), irrespective of any
effect of individual muscle length change, simply because of a change of
emphasis on certain muscles that is caused by the greater ROM.
Mechanical loading can involve tensile force being developed within both the
active and passive structures of the muscle. Different ROMs could lead to
differences in mechanical loading insofar as full ROMs tend to involve force
production at longer muscle lengths. Thus, there is an element of stretch (and
therefore force production by the passive tissues) in the full ROM conditions that
is not present in the partial ROM conditions. This idea was explored by McMahon
et al. 2014, who compared the long-term effects two otherwise identical
resistance training programs using a single-joint exercise, the knee extension,
where one involved a limited ROM using a stretched position (40 90 degrees
knee angle) and the other involved a limited ROM using a contracted position (0
50 degrees knee angle). The excursion of the muscle and the mechanical load at
the tendon was equated in both conditions. Anatomical CSA of the vastus lateralis
measured using ultrasound increased significantly more in the stretched position
condition than in the contracted position condition. McMahon et al.
2014 suggested that their results might be explained by the combination of
increased muscle activity and reduced oxygen content that has been observed at
longer muscle lengths (implying greater mechanical load and metabolic stress,
respectively) and that the effect may have been mediated by a greater IGF-1
release that was observed.
While it is indeed the case that EMG activity of the quadriceps is greater at long
muscle lengths than at short muscle lengths (Kooistra et al. 2006; Kooistra et al.
2008), muscle activation measured using EMG has a strong relationship with force
production (Lawrence and DeLuca, 1983). However, McMahon et al. 2014 equated
force production at the tendon by using a lower relative load (55% of 1RM) for the
stretched position condition than for the contracted position condition (80% of
1RM).
Moreover, while muscle activation measured using fMRI has been associated with
specific increases in muscular CSA even within a muscle (Wakahara et al. 2012;
Wakahara et al. 2013) and there indeed are good correlations between muscle
activation measured using fMRI and using EMG (Dickx et al. 2010), Miyamoto et
al. (2013) reported that regional differences in vastus lateralis muscular
hypertrophy are likely better explained by the regional differences in muscle
oxygenation rather than regional differences in EMG activation. Indeed, several
studies have reported that fatigue resistance is less and oxygen consumption is
higher during isometric muscle actions in stretched positions in comparison with
contracted positions for the quadriceps (De Ruiter et a. 2005; Kooistra et al. 2006;
Debrosses et al. 2006; Kooistra et al. 2008). This may imply that greater
metabolic demand is the key factor for the observed additive effects of stretch
and contractile activity.
-

The extent to which molecular signalling for hypertrophy differs between large
and small ROM resistance training programs is unclear. Assuming that the
differences between full and partial ROM exercises are stretch-mediated, then it
may be useful to look at the differences in molecular signalling between
resistance training programs at different muscle lengths but with similar ROMs.
Additionally, it may be helpful to consider the effects of passive stretch on
molecular signalling in respect of hypertrophy.
As noted above, McMahon et al. (2014) directly compared the long-term effects of
two otherwise identical resistance training programs, where one used a stretched
position and the other used a contracted position. It was found that IGF-1 levels
increased to a greater extent following the resistance training program in the
stretched position condition, which may have mediated the larger increase in
muscle mass. Indeed, previous studies have observed increases in IGF-1 following
stretched and hypertrophied muscles (Yang et al. 1996) and it has been proposed
that locally-produced IGF-1 is a key mediating factor for stretch-mediated
muscular hypertrophy (see reviews by Goldspink, 1999; De Deyne,
2001; Philippou et al. 2007; Philippou et al. 2009).
There are at least three ways in which passive stretch could lead to molecular
signalling events that ultimately cause muscle protein synthesis and hypertrophy:
mechanoreceptors (possibly integrins, located in the costameres), growth factors
(including IGF-1 and MGF) as discussed above, and stretch-activated ion channels,
which appear to be mechanosensitive and cause alterations in ion flux (De Deyne,
2001). While the role of integrins has been implicated in the detection of
mechanical tension during active muscle actions (see review by Schoenfeld,
2010), the roles of growth factors (see reviews by Goldspink, 1999; De Deyne,
2001; Philippou et al. 2007; Philippou et al. 2009) and stretch-activated ion
channels (see review by Mohammad et al. 2011) potentially have a more specific
mode of action in that they may only be activated following lengthening of the
muscle.
Insofar as the Akt-mTOR pathway is concerned, researchers have found that
passive stretch leads to significant increases in the phosphorylation of
Akt (Sakatomoto et al. 2003; Russ, 2008), although active stretch appears to
cause greater increases (Russ, 2008), suggesting that passive stretch and
contractile activity are additive in their effects through this pathway.
PROBLEMS
to fix are those that have been found to have the biggest effect on hypertrophy
(i.e. volume). In the case of ROM, it is relatively easy to equalize volume,
particularly where volume is defined as the number of repetitions of the same

relative load.
Ecological validity
In the research literature exploring the effect of ROM on hypertrophy, there are
two types of study. One type compares the effect of training through an arbitrary,
partial ROM in a machine exercise with a full ROM of the same exercise. The other
explores the effect of training through a partial ROM in a free-weight exercise with
a full ROM of the same exercise. In this latter type of study, the partial ROM
variation enables the use of a much greater load than the full ROM equivalent
because of the torque-angle curve.
For example, in the conventional back squat, the torque-angle curve
increases steeply with increasing hip or knee angle (i.e. increasing squat depth).
This is because the external moment arms at the hip and knee increase steeply
with increasing hip and knee angle (i.e. increasing squat depth), while the load
stays the same.
Arguably, performing free-weight exercises through a partial ROM is
how individuals actually use smaller ROMs in resistance-training. Individuals
generally stop slightly short of full squat depth. There is therefore a discrepancy
between a portion of the research literature and general practice, indicating a
lack of ecological validity.
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained through a larger
ROM than the other group. Studies were sought that used the same exercises and
used equal or near equal training volumes. Outcome measures were rejected
where muscular hypertrophy was measured using arm or thigh circumference as
these were considered to be too easily affected by alterations in fat mass.
-
EFFECT OF ROM ON HYPERTROPHY (UNTRAINED)
Comparisons
Durat
ion
Larger
ROM
significant
ly better?
40 young,
untrained
males
Full ROM (0 130 degrees) vs. partial

ROM (50 100 degrees) preacher curl
10
week
s
No
difference
between
groups
Full = 9.52% and par
Bloomquist
(2013)
Muscular CSA
using MRI
scans (front
and rear
thigh)
24 young,
untrained
males
Full ROM (0 120 degrees knee flexion)

vs. partial ROM (0 60 degrees knee
flexion) squat
12
week
s
Full ROM
superior to
partial
ROM
Full ROM = 4 7% an
McMahon
(2013)
Muscular CSA
(vastus
lateralis)
using
ultrasound
26
recreationally
active
subjects
Full ROM (0 90 degrees knee flexion)

vs. partial ROM (0 50 degrees knee
flexion) of the squat, leg press and leg
extension
8
week
s
Full ROM s
uperior to
partial
ROM
At 75% of femur leng
Study
Outcome
measure for
hypertrophy
Population
Pinto
(2012)
Muscle
thickness
using
ultrasound
(elbow
flexors)

For untrained individuals, a larger ROM appears to lead to
greater hypertrophy than a shorter ROM.
For trained individuals, there is unfortunately currently
no evidence available.
-
BAR SPEED (TIME UNDER

TENSION)
PURPOSE
This section explores whether training with faster bar speeds is superior
to training with slower bar speeds for hypertrophy. This is achieved by
looking at long-term studies that compare whether a program where
subjects train with fast bar speeds is better than a program where
Absolute difference
subjects train with slower bar speeds for increasing muscular mass or
size.
BACKGROUND
Definitions
Resistance training exercises can be performed either maximally or submaximally. When performed maximally, the force-velocity relationship is relevant.
The force-velocity relationship is the observation that when greater absolute
moment is generated at a joint, the angular velocity of that joint must be lower.
Force-velocity relationships at joints are largely exponential, with force decreasing
very quickly with increasing angular velocity past a certain point.
When performed sub-maximally, the force-velocity relationship is not relevant. In
fact, as Fisher and Smith (2012) have noted, when performed to muscular failure,
a greater number of repetitions are possible with faster bar speeds (i.e.
shorter repetition durations) than with slower bar speeds (i.e. longer repetition
durations). This in turn suggests that effort and fatigue levels are greater with
slower bar speeds (i.e. longer repetition durations).
Popular usage
In practice, most resistance training is performed at sub-maximal speeds. Indeed,
most bodybuilders deliberately perform slow, controlled repetitions at submaximal speeds in order to focus on time-under-tension.
Literature usage
The comparison of different sub-maximal speeds (or maximal with sub-maximal
speeds) has been a predominant focus of research.
-
MECHANISMS FOR HYPERTROPHY IN RELATION

TO BAR SPEED

The main stimulus for hypertrophy is thought to be the application of external
mechanical load to a joint, which results in tensile force within the muscle.
A greater relative load might be expected to require a activation of a greater
number of motor units and thereby create a larger hypertrophic stimulus.
However, since deliberately slower bar speeds (leading to longer repetition
durations) involve lower relative loads, less force might be expected. This smaller
force might lead to less hypertrophy.
On the other hand, greater hypertrophic stimulus is thought to arise from more
prolonged periods in which the muscle is subjected to mechanical load. Hence,
greater time-under-tension subsequent to slower sub-maximal bar speeds (longer
repetition durations) might be assumed to be more effective than faster submaximal bar speeds (shorter repetition durations), as they involve a longer
duration of time during which the muscle is exposed to the stimulus.

stress (see reviews by Schoenfeld, 2010; Schoenfeld, 2013). There is a clear
mechanism by which longer repetition durations could lead to increased
metabolic stress, as muscular contractions above a certain (fairly low) threshold
of maximum voluntary isometric contraction force prevent venous return. Since
metabolic stress arises primarily from the prevention of venous return and the
consequent buildup of metabolites such as blood lactate, intramuscular lactate,
glucose and glucose-6-phosphate within the muscle, longer repetition durations
would be expected to lead to greater metabolic stress and consequently greater
hypertrophy, so long as all other factors remained constant.
In summary, slower bar speeds (causing longer repetition
durations) might be less effective than faster bar speeds (causing
shorter repetition durations) because they involve lower relative loads.
On the other hand, slower bar speeds might be more effective than
faster bar speeds for hypertrophy on the basis that the tensile force in
the muscle is longer in duration. Additionally, the longer period of time

in which the muscle is subjected to metabolic stress when using slower
bar speeds might also be expected to lead to increased hypertrophy.
-

There are some indications that a longer time under tension
may enhance molecular signalling pathways for hypertrophy, although
the literature is limited and confounded in human trials by muscular
failure.
Study
Comparison
Pathw
ay
Population
Finding
Martinea
u (2002)
Four passive stretch protocols of equal excursion but with different speeds
of stretch (and therefore time under tension)
MAPK
Rodent model
Linear relation
Roschel
(2011)
Eccentric muscle actions comprising 5 sets of 8 repetitions at either slow (20

degrees/s) or fast (210 degrees/s) speeds
mTOR
20 untrained subjects
No difference
Burd
(2012)
Muscle actions comprising 3 sets with 30% of 1RM in either slow (6-second)
to failure or work-matched fast but not to failure (1-second) conditions
mTOR
8 recreationally
resistance-trained
males
Slow increased

There are some indications that time under tension may be important
for maximizing muscle protein synthesis post-workout, although the
literature is very limited at present.
Study
Comparison
Outcome
Population
Burd
(2012)
Muscle actions comprising 3 sets with 30% of 1RM in either

slow (6-second) to failure or work-matched fast but not to
failure (1-second) conditions
Muscle
protein
synthesis
8 recreatio
resistance
males
PROBLEMS
The force-velocity relationship is a serious confounding factor when comparing
groups training with different maximal bar speeds. This is because the group
training with the faster bar speed must use a lighter relative load. This means
that relative load is different between the two conditions. However, when
comparing two groups training with different sub-maximal bar speeds, the forcevelocity relationship is normally not a problem. This is because the same relative
load (for the bar speed) can be used in both cases. It is expected that in order to
use slower sub-maximal bar speeds (longer repetition durations) the effort and
fatigue are significantly greater than in faster sub-maximal bar speeds (shorter
repetition durations. Therefore, it is anticipated that the absolute loads will be
smaller for the same relative load in the slower sub-maximal bar speed
conditions.
Whether the same relative load is actually used is another matter. Indeed, the two
studies reported below by Watanabe (Watanabe et al. 2013 and Watanabe et al.
2013a) compare two protocols that used different relative loads for the bar speed
by using the same absolute load.
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained using a slower bar
speed (longer repetition duration) than the other. Studies were sought that used
the same exercises and used equal or near equal training volumes. Outcome
measures were rejected where muscular hypertrophy was measured using arm or
thigh circumference as these were considered to be too easily affected by
alterations in fat mass.
-
EFFECT OF BAR SPEED ON

Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Slower bar sp
better?
Young
and Bilby
(1993)
Muscle thickness
measured by
ultrasound
18 healthy but
untrained males,
aged 19 23 years
Fast (controlled eccentric and explosive concentric)

vs. Slow (controlled eccentric and concentric)
7.5
weeks
No difference
Keeler
(2001)
Lean body mass

using Bod Pod
14 healthy,
sedentary women,
Slow (2s concentric and 4s eccentric) vs. SuperSlow

(10s concentric and 5s eccentric)
10 weeks
No difference
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Slower bar sp
better?
aged 19 45 years
Neils
(2005)
Lean body mass

using DEXA
scans
19 healthy but
untrained males
and females, aged
18 30 years
Slow (2s concentric and 4s eccentric) with 80% of 1RM

vs. SuperSlow (10s concentric and 5s eccentric) with
50% of 1RM
8 weeks
No difference
Tanimoto
and Ishii
(2006)
Muscular CSA
(thigh) using
MRI scans
24 healthy but
untrained males,
aged ~ 20 years
Slow (3s eccentric and concentric) with 50% of 1RM vs.

fast (1s eccentric and concentric) with 80% of 1RM
12 weeks
No difference
Tanimoto
(2008)
Muscle thickness
using ultrasound
36 healthy but
untrained males,
aged ~ 20 years
Slow (3s eccentric and concentric) with 50% of 1RM vs.

fast (1s eccentric and concentric) with 80% of 1RM
13 weeks
No difference
Watanabe
(2013)
Muscle
thickness(thigh)
using ultrasound
35 elderly
individuals, aged
59 76 years
Slow (3s eccentric and concentric) and fast (1s

eccentric and concentric) with the same relative load
(50% of 1RM)
12 weeks
Slow superior
Watanabe
(2013a)
Muscle CSA
(thigh) using
MRI scans
18 elderly
individuals,
aged 60 77 years
Slow (3s eccentric and concentric) and fast (1s

eccentric and concentric) with the same relative load
(30% of 1RM)
12 weeks
Slow superior

For untrained individuals, deliberately slowing down bar
speed to increase time under tension seems to make little
difference to hypertrophy.
For trained individuals, there is unfortunately currently
no evidence available.
-
MUSCLE ACTION (VARIABLE)

PURPOSE
This section explores whether training with eccentric muscle actions is
superior to training with concentric muscle actions while using isokinetic
(i.e. variable) external resistance for hypertrophy. This is achieved by
looking at long-term studies that compare isokinetic resistance
training programs involving eccentric-only muscle actions are better
than isokinetic resistance training programs involving concentric-only

muscle actions for increasing muscular mass or size.
BACKGROUND
Definitions
Eccentric vs. concentric muscle actions
Muscles can be either active or passive, depending upon whether neural signals
are sent to them. While being either active or passive, they can either lengthen,
shorten, or remain the same length. Shortening active muscles are called
concentric muscle actions, lengthening active muscles are called eccentric muscle
actions, and when active muscles remain the same length, these are called
isometric muscle actions.
Isometric muscle actions can be further divided into either yielding or overcoming
isometric muscle actions. Yielding isometric muscle actions involve holding a load
static, although it would be feasible to perform a concentric muscle action with it
if force production were increased. An example of a yielding isometric muscle
action might be pausing with the barbell at the bottom of the lift during a bench
press. Overcoming isometric muscle actions involve exerting maximum force
against and immovable object. An example of an overcoming isometric muscle
action might be pushing a barbell into the pins of a rack in the bench press. There
is no possible way that the barbell could be moved through the pins.
Variable load vs. constant load external resistance

External resistance can initially be categorized into two overall categories: (1)
external resistance that remains constant throughout a muscle action, (2)
external resistance that varies throughout a muscle action. Within the first overall
category of external resistance, the two main types are isoinertial and isometric.
Isoinertial resistance is simply an object with mass that can be lifted. The mass
remains the same at all time and any variation that occurs in how hard it is to lift
throughout the joint range of motion depends entirely on the internal or external
moment arms. Isometric external resistance is essentially a subcategory of
isoinertial resistance but where the mass is too heavy to lift and it therefore
becomes an immovable object.
Variable, isokinetic and accommodating external resistance

Within the second overall category of external resistance, the two main types are
variable and isokinetic. Variable resistance is simply where the resistance changes
with joint range of motion in an unspecified way. Isokinetic resistance is
essentially a subcategory of variable resistance but the way in which the
resistance changes is so as to maintain a constant velocity throughout the joint
range of motion. Isokinetic resistance thereby corrects for the internal and
external moment arms at all points. Accommodating resistance is technically
identically to isokinetic resistance in biomechanical definitions. However, in
popular usage (usually in powerlifting environments) it often refers to merely an
approximation to isokinetic by the use of bands or chains. In such set-ups, the
term variable resistance is more correct.
Popular usage
Despite the great interest in the research literature for eccentric muscle actions
for their potential to increase hypertrophy, bring about increased muscle lengths
through sarcomerogenesis, and treat various musculoskeletal conditions,
including tendinopathy, they have not been widely used by the general public or
by the bodybuilding community.
Literature usage
Researchers have investigated eccentric muscle actions extensively for their
potential to increase hypertrophy, bring about increased muscle lengths through
sarcomerogenesis, and treat various musculoskeletal conditions, including
tendinopathies (mainly of the Achilles tendon).
META-ANALYSES
Findings
Roig et al. (2009) performed a meta-analysis to assess the effect of muscle

action on hypertrophy. Roig et al. (2009) analysed 20 randomized controlled trials
involving both isokinetic and isoinertial external resistance. They reported that
when eccentric exercise was performed using higher relative loads, there was a
significantly greater effect on hypertrophy, when muscular size was measured as
muscle girth and there was a trend in the same direction when muscular size was
measured using either MRI or CT scans.
-

MUSCLE ACTION

There are several mechanisms through which eccentric-only training might lead
to superior results to concentric-only or stretch-shortening cycle training, all of
which involve an increase in mechanical loading. Firstly, eccentric-only training
involves a lower energy cost for the same tensile forces being experienced within
the muscle (e.g. Peailillo, 2013). In this way, lifters are able to perform a greater
volume of work while taxing their work capacity to the same degree (thereby
involving a greater mechanical loading stimulus). A second point that is related to
this is that eccentric-only training enables lifters to move a larger amount of
weight than during concentric-only or stretch-shortening cycle muscle actions
with the same percentage of 1RM (e.g. Flanagan, 2013; and Moir, 2013), which
therefore involves greater absolute mechanical loading. These greater tensile
forces arise because passive structures within the contractile elements of muscle
fibers contribute to the mechanical tension that is developed by the active
structures (Schoenfeld, 2010). Passive structures are thought to involve those
external to the muscle fiber (i.e. the extracellular matrix) and also those internal
to the muscle fiber (i.e. the giant molecule titin).
Thirdly, eccentric muscle actions are thought to lead to greater exercise-induced

muscle damage than concentric muscle actions, which may arise either because
of the greater tension or because of the nature of the tension in that it is exerted
while the muscle is lengthening. Exercise-induced muscle damage may be one
mechanism by which hypertrophy is stimulated (see review by Schoenfeld, 2010).
However, whether this factor is as important as has previously been reported is a
matter of debate (see review by Schoenfeld, 2012). Muscle damage subsequent
to eccentric muscle actions can be very small in nature or it can involve
significant tears in the muscle. The phenomenon of muscle damage appears to
bear some similarities with initial inflammatory responses to infection
(Schoenfeld, 2010) insofar as the damaged muscle emits agents that attract
macrophages and lymphocytes, which clear up the cellular debris. Agents are also
released that lead to the release of growth factors regulating the proliferation and
differentiation of satellite cells and consequently the repair of the muscle damage
and the provision of new nuclei for the muscle fibers (Schoenfeld, 2010).
Finally, it seems that eccentric muscle actions may target the fast-twitch muscle
fibers to a greater degree than concentric muscle actions (e.g. Hortobagyi,
2000; and Hortobagyi, 1996) and these muscle fibers are known to have greater
capacity for growth. This may be mediated by the tensile forces involving the
passive structures leading to a different signalling response (Tannerstedt et al.
2009; review by Schoenfeld, 2010) although there is also evidence that signalling
differs between type I and type II muscle fibers irrespective of muscle action
(Koopman et al. 2006).
In summary, eccentric muscle actions might be more effective than
concentric muscle actions for hypertrophy because they (1) allow
greater mechanical tension to be developed, (2) permit a greater volume
of training to be performed, (3) lead to greater muscle damage, and
(4) lead to more tension in the passive structures, which may trigger
greater growth in type II muscle fibers.
-
Eccentric muscle actions may lead to different molecular signalling

responses for hypertrophy than concentric muscle actions, both
irrespective of muscle fiber type, and specifically in type II muscle fibers.
Study
Comparison
Pathway
Population
Finding
Martineau
(2001)
Eccentric vs. concentric muscle actions
MAPK
Rodent
model
Eccentric displayed greater ERK1 and JNK phosphorylati
Eliasson
(2006)
Isokinetic eccentric vs. concentric

muscle actions, matched for (1) relative
and (2) absolute force
mTOR
10 healthy
but
untrained
males
Matched for relative force, eccentric displayed greater

phosphorylation of Akt and mTOR
Cuthberts
on (2006)
Isoinertial eccentric vs. concentric

muscle actions with the same absolute
load
mTOR
8 healthy
but
untrained
males
No differences in respect of phosphorylation of Akt and
Rahbek
(2014)
Isokinetic eccentric vs. concentric

muscle actions
mTOR
24 healthy
subjects
Phosphorylation of mTOR, p70S6k and rpS6 was of longe

Eccentric muscle actions may lead to greater levels of acute muscle
protein synthesis but this may depend on whether relative load is
matched.
Study
Comparison
Outcome
Population
Finding
Moore
(2005)
Isokinetic eccentric vs. concentric muscle actions, matched for

total workload
Muscle protein
synthesis
8 healthy young
males
Muscle protein s
Cuthbertson
(2006)
Isoinertial eccentric vs. concentric muscle actions with the

same absolute load
Muscle protein
synthesis
8 healthy but
untrained males
No differences i
Rahbek
(2014)
Isokinetic eccentric vs. concentric muscle actions
Muscle protein
synthesis
24 healthy subjects
No differences i
PROBLEMS
Owing to the differences in energy cost and absolute force production between
eccentric and concentric muscle actions, it is not an easy matter to control all of
the other key variables, particularly volume and relative load. The use of
isokinetic external resistance makes this issue even more complex, as force
production varies constantly throughout a single repetition, across repetitions of
the same set, and between conditions while the velocity does not.
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained using
predominantly or exclusively eccentric muscle actions while the other trained
predominantly or exclusively using concentric muscle actions, where the external
resistance used was isokinetic. Studies were sought that used the same exercises
and used equal or near equal training volumes.
-
EFFECT OF MUSCLE ACTION ON

Study
Outcome
measure for
hypertrophy
Population
Comparisons
Seger
(199
8)
Muscular CSA
(distal and
middle
quadriceps)
using MRI scans
10 moderatelytrained physical
education
students
Eccentric vs.
concentric at 90
degrees/s
Duration
10
weeks
Eccentric significantly better?
Distal: eccentric superior to concentric. Mid-point: no

differences between groups

Study
Outcome measure
for hypertrophy
Population
Komi
and
Buskirk
(1972)
Muscular girth of
upper arm
31 untrained
males
Mayhew
(1995)
Higbie
(1996)
Hortoba
gyi
(1996)
Hortoba
Comparisons
Durati
on
Eccentric
significantly
better?
Absolute differences
Eccentric vs.
concentric
7
weeks
Eccentric superior
to concentric
Eccentric = 0.57 0.68cm and
Concentric/eccentric: type II
Fiber CSA
20 untrained
males and
females
Eccentric vs.
concentric at
30 degrees/s
4
weeks
Type II: concentric

superior to
eccentric. Type I:
no differences
between groups
Muscular
CSA (quadriceps)
using MRI scans
54 untrained
females
Eccentric vs.
concentric
10
weeks
Eccentric superior
to concentric
Eccentric = 6.0 7.8% and con
Type I/II: eccentric = 14.4 4.

Eccentric/concentric: Type I,
Fiber CSA
21 sedentary
males, aged ~ 22
years
Eccentric vs.
concentric
12
weeks
Type II:
eccentric superior
to concentric.
Type I: no
differences
between groups
Fiber CSA
48 recreationally
Eccentric vs.
12
Eccentric superior
Study
Outcome measure
for hypertrophy
Durati
on
Eccentric
significantly
better?
Absolute differences
weeks
to concentric
(types I, IIa and
IIx)
16%/5%
Eccentric-fast = 13 2.5%, con

and concentric-slow = 5.3 1.
Population
Comparisons
active males and

females, aged 22
3 years
concentric at
60 degrees/s
Muscle thickness
(elbow flexors)
using ultrasound
36 males and
females
Eccentric vs.
concentric at
slow (30
degrees/s) or
fast (180
degrees/s)
speeds
8
weeks
Fast: eccentric
superior. Slow: no
differences
between groups
NickolsRichards
on
(2007)
Lean body mass

using DEXA
70 healthy but
untrained
females, aged 18
26 years
Eccentric vs.
concentric at
60 degrees/s
5
month
s
No difference
between groups
Concentric = 0.6kg (1.5%) and
Blazevic
h
(2007)
Muscular CSA
(quadriceps) using
MRI scans
21 males and
females
Eccentric vs.
concentric at
30 degrees/s
10
weeks
No difference
between groups
Absolute increases not disclos
Moore
(2012)
Muscular CSA
(biceps brachii)
using CT scans
9 healthy,
recreationally
active males,
aged 22 1 years
Eccentric vs.
concentric at
45 degrees/s
9
weeks
No difference
between groups
Eccentric = 6.5 0.6% and co
Muscular CSA
(quadriceps) using
MRI scans
16 elderly males,
aged 60 70
years
Eccentric at
30 degrees/s
vs. stretchshortening
cycle (SSC)
10
weeks
No difference
between groups
Eccentric = 3.1% and SSC = 2.1
Cadore
(2014)
Muscle thickness
(vastus lateralis)
using ultrasound
22 healthy and
physically males
and females,
aged ~ 22 years
Eccentric vs.
concentric at
60 degrees/s
6
weeks
No difference
between groups
Eccentric = 12.2 8.1% and co
Kim
(2014)
Muscle thickness
(supraspinatus)
using ultrasound
14 recreationally
active males and
females, aged 18
50 years
Eccentric vs.
concentric at
60 degrees/s
8
weeks
No difference
between groups
Eccentric = 0.2cm and concen
gyi
(2000)
Farthing
(2003)
Vczi
(2014)

For trained individuals using variable-load external resistance, there is limited
evidence that eccentric muscle actions might be superior to concentric muscle actions.
For untrained individuals using variable-load external resistance, there
is conflicting evidence that eccentric muscle actions might be superior to concentric
muscle actions.
MUSCLE ACTION (CONSTANT LOAD)

PURPOSE
This section explores whether training with eccentric muscle actions is

superior to training with concentric muscle actions while using
isoinertial external resistance (i.e. constant load) for hypertrophy. This
is achieved by looking at long-term studies that compare whether
isoinertial resistance training programs involving eccentric-only muscle
actions are better than isoinertial resistance training programs involving
concentric-only muscle actions for increasing muscular mass or size.
BACKGROUND
See previous section: Muscle action (isokinetic)
MECHANISMS FOR HYPERTROPHY

See previous section: Muscle action (isokinetic)
PROBLEMS
Owing to the differences in energy cost and absolute force production between
eccentric and concentric muscle actions, it is not an easy matter to control all of
the other key variables, particularly volume and relative load.
When comparing eccentric and concentric muscle actions across two groups,
there are two common options for equating the load used in each group. Either
the same absolute load can be used in both groups or the same relative load can
be used in both groups. Another, less-common option is to use an arbitrary,
heavier load in the eccentric group.
Where the same absolute load is used in both eccentric and concentric groups,
this means that the relative load is lower in the eccentric condition (as muscles
are stronger during eccentric muscle actions than during concentric muscle
actions). Thus, relative load becomes a confounding factor in the investigation.
Where the same relative load is used, this eliminates relative load as a
confounding factor. However, if the same set and repetition scheme is then
employed between the eccentric and concentric groups, then (depending on how
you define volume) this leads to an excess of volume being performed in the
eccentric condition than in the concentric condition (because the absolute load is
greater).
SELECTION CRITERIA
>2 resistance-training programs, where 1 of the groups trained using
predominantly or exclusively eccentric muscle actions while the other trained
predominantly or exclusively using concentric muscle actions, where the external
resistance used was isoinertial. Studies were sought that used the same exercises
and used equal or near equal training volumes.
-

Study
Outcome measure for

hypertrophy
Population
Comparisons
Duration
Vikne
(2006)
Muscular CSA (elbow flexors)

using CT scans
17 resistance-trained
males
Eccentric (over 3 4s) vs. concentric

(explosive)
12 weeks
EFFECT OF MUSCLE ACTION ON HYPERTROPHY (UNTRAINED)

Study
Outcome measure for

hypertrophy
Population
Comparisons
Durati
Ben-Sira
(1995)
Thigh girth measured with

a tape measure
60 untrained, young female

students
Eccentric vs. supra-maximal

eccentric (130% of concentric
1RM) vs. concentric
8 wee
Reeves
(2009)
Muscle thickness (vastus

lateralis) using ultrasound
19 untrained males and

females, aged 74 3years
Eccentric vs. stretch-shortening

cycle
14 we
Smith
(1995)
Muscular CSA
(quadriceps) using CT
scans
10 males and females,

aged ~ 20 years
Eccentric vs. concentric
20
week
Study
Outcome measure for

hypertrophy
Population
Jones
(1987)
Muscular
CSA (quadriceps) using
CT scans
Farup
(2013)
Comparisons
Durati
Eccentric (145% of
concentric) vs.
concentric
6 young males and females
12
week
Muscular CSA using MRI scans
Eccentric vs. concentric (with and

without whey protein
supplementation)
22 healthy but untrained males, aged

23.9 0.8 years
12 week
Franchi
(2014)
Muscular volume using MRI

scans
Eccentric vs. concentric (with

and without whey protein
supplementation)
12 young males
10 wee
Farup
(2014)
Fiber CSA
Eccentric vs. concentric
22 healthy but untrained males, aged

23.9 0.8 years
12 week

For trained individuals using constant-load external
resistance, there is limited evidence that eccentric muscle
actions might be superior to concentric muscle actions.
For untrained individuals using constant-load external
resistance, there does not seem to be any difference
between eccentric and concentric muscle actions.
-
PERIODIZATION
PURPOSE
This section investigates whether periodization is effective for
compare whether a periodized program is better than a non-periodized
program for increasing muscular mass or size. The section

also investigates which periodized program is best for muscular
compare different types of periodized program and their effects on
either muscle mass or size.
BACKGROUND
Definitions
The term periodization has historically been notoriously difficult to define with
any degree of precision or consensus. However, in this analysis, periodization will
be defined as the structure of a training program, where this training program
varies over time, either linearly, non-linearly, or in blocks, in order to maximize
the results of the athlete. In contrast, a non-periodization training program
will be defined either as a non-varied program or a program that varies randomly.
Any training variable can be periodized (i.e. exercise selection, relative-load,
volume, frequency, range-of-motion, proximity to failure, rest periods, etc.).
However, in practice the two most commonly-varied training variables are relative
load and volume. Typically, volume is reduced while relative load is increased and
vice versa.
Periodization types
Introduction
Periodization types fall into three main categories: linear, non-linear, and block. In
brief, linear (and reverse linear) periodization involves sequential alteration of key
training variables over time. Non-linear periodization involves altering training
variables from day-to-day or from week-to-week such that all training variables
are used similarly within short periods of time. Block periodization involves
training for a specific goal in successive, additive cycles.
Linear periodization
Linear periodization is the traditional and earliest form of periodization. This was
originally proposed by Matveyev in the 1950s and involves a steady progression
from high-volume, low-relative load training at the start of the program through to
low-volume, high-relative load training at the end. A variant of linear periodization
is reverse linear periodization in which the opposite sequence is followed. It is
worth noting that volume and relative load are the most commonly manipulated
training variables but essentially there is no reason why other variables cannot
also be periodized, such as frequency, range-of-motion, proximity to failure, rest
periods and exercise selection. For example, escalating density training (a method
of training put forward by Charles Staley that involves steadily reducing rest
periods over a period of time) is essentially a form of linear periodization in which
a training variable (rest periods) is altered progressively over time.
Non-linear periodization
Non-linear periodization, which encapsulates methods known as undulating
periodization and conjugate periodization, involves a less sequential change in
training variables than linear periodization over the course of a training cycle. In
non-linear periodization, workouts are arranged with training variables being
altered across multiple workouts over short periods. This can occur from day-today over the course of a single week of workouts (daily undulating periodization)
or from week-to-week over the course of several weeks of workouts (weekly
undulating periodization). As noted above, while volume and relative load are
most commonly investigated and manipulated over the course of periodized
programs, there is no reason why exercise selection cannot be changed in the
same way. This can be seen in the Westside method, where different exercises are
rotated frequently throughout a training cycle.
Block periodization
Block periodization was proposed by Verkoshansky (1998) and involves cycles of
sequential training designed to achieve a specific goal. Each block is intended to
be the foundation for the next one. Depending on the terminology used, a typical
sequence of cycles would be accumulation, transformation and realization, which
are elsewhere called hypertrophy, maximal strength and power. The progression
from high-volume, low-relative load to lower-volume and higher-relative loads
makes it easy to confuse with linear periodization but the premise behind block
periodization is different and involves a focus on the goal of the training cycle
rather than just the sets and reps. For a discussion of the differences between
block and traditional linear periodization, see Issurin (2008).
-

PERIODIZATION

Introduction
The two primary mechanisms for bringing about hypertrophy are mechanical
loading and metabolic stress. It is unclear precisely how periodization helps to
maximize either of these two mechanisms.
General Adaptation Syndrome

Although it seems that periodization was adopted prior to the existence of an
evidence base, researchers have since proposed at least two plausible
mechanisms to support existing practice. The majority of commentators on
periodization reference Selyes General Adaptation Syndrome (see further Haff,
2004).
Indeed, it does seem logical that by incorporating changes to the program
variables (e.g. relative load, volume, exercises, etc.), this would cause the
neuromuscular systems to be exposed to unaccustomed stressors. However, as
noted above, it is unclear precisely how this relates to mechanical loading or
metabolic stress. Similarly, it seems sensible that by failing to introduce variation,
continued improvements are likely to cease. However, this mechanism only
suggests that variability is necessary and does not account for the proposed need
for structure within the concept of periodization.
Sequenced potentiation
In addition to the General Adaptation Syndrome, researchers working in the area
of periodization also refer to the mechanism of sequenced potentiation (see
further Haff, 2004) to provide further support to the logical structure that is used
in periodized models. Sequenced potentiation suggests that building a foundation

of strength with heavy loads allows individuals to maximize the gains they can
achieve from power-training with lighter loads. Similarly, hypertrophy-training
might be achieved more quickly in stronger individuals, where a foundation of
strength has already been built. This interesting idea may support the idea of
block periodization but does not lend strong conceptual support to other methods,
such as traditional linear periodization or non-linear methods that vary loading
schemes very regularly.
PROBLEMS
Ecological validity
Periodization is very difficult to study in practice, making our ability to draw
conclusions from the literature limited. Many researchers and coaches have
drawn attention to the limitations of the current literature (e.g. Cissik, 2008),
which has not kept pace with research in other areas, such as the effects of
certain training variables on strength gains (e.g. relative load, volume, etc.).
Primarily, Cissik (2008) observed that it is problematic that the majority of
available studies are short-term in nature (approximately the duration of an
academic semester), use non-athletic college populations, and primarily involve
strength training modalities only. Cissik therefore suggested that this makes it
difficult to the current periodization research to athletic populations who structure
their training plans over years and performed concurrent training modalities. For
the purposes of applying the available research to the achievement of strength
gains during recreational resistance-training, however, these are not large
concerns.
Methodological validity
More concerning for the application of the available research to recreational
resistance-training was raised in a brilliant paper by Kiely (2012), who pointed out
most experimental designs exploring periodization have actually simply compared
varied with non-varied interventions. Thus, such studies simply demonstrate that
variation is important, and not that periodization is the best way of providing this
variation. This relatively simple but radical criticism has unfortunately not been
developed since it was raised in 2012. However, until a high quality study
compares a randomized program with a periodized program and with a non-varied
program, we will continue to lack an understanding of whether variation or
structured periodization are of greater importance.
SELECTION CRITERIA
>2 resistance-training programs, where >2 of the programs followed a commonlyused (but different) periodization model or where there was a periodization model
and a non-periodized control group. Studies were sought that used the same
exercises and used equal or near equal training volumes.
-
EFFECTS OF PERIODIZED VS. NON-PERIODIZED

PROGRAMS ON HYPERTROPHY (TRAINED)
Study
Outcome measure
for hypertrophy
Population
Comparisons
Duration
Baker
(1994)
Lean body mass

estimated using
skin-fold callipers
22
trained male
athletes
Linear periodized, nonlinear (undulating)

periodized, and nonperiodized programs
12
weeks
Monteiro
(2009)
Lean body mass

estimated using
skin-fold callipers
27 strengthtrained males
Non-periodized, linear
periodized and non-linear
periodized programs
12
weeks
EFFECTS OF LINEAR VS. NON-LINEAR

PROGRAMS ON HYPERTROPHY (TRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Line
perio
bett
Baker
Lean body mass
22 experienced
Linear periodized,
12
No d
Study
(1994)
Monteiro
(2009)
Prestes
(2009)
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Line
perio
bett
male athletes
non-linear
(undulating)
periodized, and nonperiodized programs
weeks
grou
Lean body mass

estimated using
skin-fold callipers
27 strengthtrained males
Non-periodized,
linear periodized, and
non-linear periodized
programs
12 week
s
No d
grou
Lean body mass

estimated using
skin-fold callipers
40 males with >1

year of
resistancetraining
experience
Linear periodized and

non-linear (daily
undulating)
periodized programs
12
weeks
No d
grou
estimated using
skin-fold callipers
EFFECTS OF LINEAR
VS. REVERSE LINEAR PROGRAMS ON
Study
Prestes
(2009)
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
L
p
b
Lean body mass

estimated using
skin-fold callipers
Females with >6

months of resistancetraining experience,
aged 20 35 years
Linear
periodized and
reverse linear
periodized programs
12
weeks
L
re
EFFECTS OF LINEAR VS. BLOCK PROGRAMS ON

Study
Bartolomei
(2014)
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Lean body mass

estimated using
skin-fold callipers
25 strength and power

athletes from track
& field throwing,
Block (hypertrophy
strength power)
vs. linear
15
weeks
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Rugby or American
football
periodization
Duration
EFFECTS OF PERIODIZED VS. NON-PERIODIZED

PROGRAMS ON HYPERTROPHY (UNTRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Stone
(1981)
Lean body mass

estimated using
skin-fold
callipers
Untrained,
college-aged
male subjects
Periodized and non-periodized

programs
6 weeks
Souza
et al.
(2014)
Muscular CSA
(quadriceps)
using MRI scans
31
recreationally
active males
Non-periodized, linear
periodized, and non-linear
(daily undulating) periodized,
matched for volume load
6 weeks
EFFECTS OF LINEAR VS. NON-LINEAR

PROGRAMS ON HYPERTROPHY (UNTRAINED)
Study
Outcome
measure for
hypertrophy
Population
Comparisons
Duration
Lin
pe
be
Kok
(200
9)
Muscle CSA
(rectus femoris)
using ultrasound
20 untrained
females
Linear periodized and nonlinear (daily undulating)

periodized programs
9 weeks
No
gr
Simo
(201
2)
Muscle thickness
(Triceps and
biceps)
using ultrasound
30 untrained
males
Non-linear (daily undulating)

and linear
periodized programs
12
weeks
No
su
pe
De
Lima
Lean body mass

estimated using
28 sedentary
females aged 20
Linear or non-linear (daily

undulating)
12
weeks
No
gr
Study
Outcome
measure for
hypertrophy
Population
Comparisons
(201
2)
skin-fold
callipers
35 years
periodized programs
31 recreationally
active males
Non-periodized,
linear periodized, and nonlinear (daily
undulating) periodized,
matched for volume load
Souza
et al.
(201
4)
Muscular CSA
(quadriceps)
using MRI scans
Duration
Lin
pe
be
6 weeks
No
gr

For trained individuals, periodization makes little
difference for hypertrophy. There is limited evidence to
suggest that reverse linear is worse than linear but linear
and non-linear approaches appear to have equal merit.
For untrained individuals, there are conflicting indications
that periodization might be superior to non-periodization
and that non-linear might be superior to linear.
-
MECHANISMS OF HYPERTROPHY
PURPOSE
This section describes the mechanisms by which hypertrophy occurs,
from the detection of the initial stimulus through the molecular
pathways that lead to an excess of muscle protein synthesis over muscle
protein breakdown, causing net protein accretion.
SECTION CONTENTS
Click on the links below to jump down to the relevant section of the page:
1.
Primary stimuli for hypertrophy
2.
Secondary stimuli for hypertrophy
3.
Molecular processes: mTOR
4.
Molecular processes: MPAK
5.
Molecular processes: Calcineurin-NFAT
6.
Molecular processes: Myostatin
7.
Molecular processes: Satellite cells
8.
Net protein accretion
PRIMARY STIMULI FOR HYPERTROPHY

Introduction
The primary stimuli for hypertrophy have been categorized in various ways.
Schoenfeld (2010) initially divided the stimuli into three main primary categories:
mechanical loading, exercise-induced metabolic stress, and muscle damage.
Pearson and Hussain (2014) later categorized the (non-pharmaceutical) stimuli
into the two primary categories of mechanical loading and exercise-induced
metabolic stress, and then described multiple secondary categories of mechanism
resulting from these, including mechanotransduction, muscular damage, systemic
and localized hormones, cell swelling, reactive oxygen species, nitric oxide, and
heat shock proteins (Pearson and Hussain, 2014).
Whether or not muscle damage is a primary mechanism for hypertrophy remains
a matter of debate and requires further research and analysis. It has been
suggested that muscle damage is a primary mechanism on the basis that it
triggers secondary mechanisms. On the other hand, it has been argued that since
muscle damage requires mechanical loading to occur, it cannot itself be a primary
mechanism, as it is dependent upon the presence of mechanical loading. The

problem may therefore lie in the definitions of primary and secondary in this
context rather than anything inherent in the biochemistry of the molecular
mechanisms involved.
It seems probable that most readers are likely to interpret the use of primary to
mean that which comes first rather than that which causes something to come
after. Therefore, although the review by Pearson and Hussain (2014) was in the
context of blood flow restriction (BFR) training, the conceptual categorization of
the primary and secondary mechanisms will be adopted in this review as the most
logical way of arranging the various stimuli at present.
-
Mechanical loading
The following diagram shows the key secondary mechanisms that result from
mechanical loading:
Introduction
The main stimulus for hypertrophy is thought to be mechanical loading of
the muscles, predominantly through the medium of external load. However, as
McMahon et al. (2014) have noted, mechanical loading can occur in conjunction
with either active muscles (involving muscle activation and subsequent force
production) or with passive muscles (as occurs during certain types of stretching).
Interestingly, mechanical loading in both active and passive muscles has been
reported to produce hypertrophy.
Active production of tensile force

loading. External mechanical load, when exerting force upon the human body,
produces a joint moment. In order to resist this joint moment, muscles acting as
agonists at the joint can generate tensile force. To produce tensile force actively
and bring about either eccentric, concentric or isometric muscle actions, a neural
signal is sent to activate motor units in the muscle, which each recruit a group of
dedicated muscle fibers. The greater the neural signal, the more motor units are
activated and consequently the more muscle fibers are recruited, thereby
producing more force (i.e. Hennemans size principle).
Hennemans size principle (see reviews by Enoka, 1984; Heckman and Enoka,
2012; Bawa et al. 2014) states that smaller and weaker motor units
(innervating few muscle fibers) are recruited before larger and stronger motor
units (innervating larger numbers of muscle fibers). This process is thought to be
automatic, insofar as the neural signal required to activate a motor unit is related
to its size. Thus, muscular activation proceeds progressively from small to large
motor units with increasing magnitude of the neural signal. However, there are
two cautionary points to note.
Firstly, Willardson (2007) has observed that care should be taken when
applying Hennemans size principle to discussions of muscular failure. Muscular
failure is by no means identical to full motor unit recruitment, as it is frequently
possible to perform repetitions with a lighter relative load once muscular failure
with a given working weight is reached. Secondly, as Bawa et al. (2014) have
observed, while orderly progression of motor unit recruitment occurs in laboratory
conditions with simple muscles and a limited number of muscle actions, some
disruptions to this rank order have been recorded. Thus, the question remains
whether the size principle of orderly recruitment applies to the more noisy,
physiological systems that are common to movements in everyday life and

sporting activity.
In addition to the magnitude of the neural signal, the duration of the neural signal
is also thought to be important. The longer the duration of the neural signal, the
longer the motor units remain activated and the longer the muscle fibers remain
recruited, thereby producing force for a longer period of time. In this way, both
greater force production and longer periods of active force production are thought
to create a greater mechanical loading stimulus.
Passive production of tensile force

loading. External mechanical load, when exerting force upon the human body,
produces a joint moment. Muscles generate tensile force passively against this
joint moment, although such forces are only of sizeable magnitude when the
muscles are stretched towards end range.
A number of studies using animal models have shown that active force generation
is unnecessary for increases in muscle mass and that passive stretching alone can
produce muscular hypertrophy (Goldspink, 1977; Holly et al. 1980; Goldspink et
al. 1995; Coutinho et al. 2004; review by Mohammad et al. 2011). Moreover,
further animal trials have found that stretching has an additive effect on both
acute muscle protein synthesis (Goldspink et al. 1995) and long-term muscular
hypertrophy when combined with force production (Goldspink et al. 1992;
Goldspink, 1999). However, it is unclear whether muscle protein synthesis is
elevated acutely in humans following passive stretching (Fowles et al. 2000).
Secondary mechanisms and molecular processes

Mechanical load is thought to lead to the activation of molecular processes that
cause elevated periods of muscle protein synthesis over muscle protein
breakdown over an extended period of time, ultimately bringing about net protein
accretion. The molecular processes are mediated by a number of key
intermediary steps (called secondary mechanisms), including
mechanotransduction, elevated local hormone production, muscle damage, and
reactive oxygen species (ROS) production (see review by Pearson and Hussain,
2014).
-
Exercise-induced metabolic stress

The following diagram shows the key secondary mechanisms that result from
elevated exercise-induced metabolic stress:
Introduction
The second main stimulus for hypertrophy is thought to be exercise-induced
metabolic stress (see reviews by Schoenfeld, 2010; Schoenfeld, 2013) resulting
from exercise relying heavily upon anaerobic glycolysis for ATP production or from
exercise performed under ischemic conditions and which actively prevents venous
return, such as blood flow restriction training. Anaerobic glycolysis leads to
the build-up of metabolites including lactate, hydrogen ions, inorganic phosphate
ions, and creatine.
Although mechanical load is generally regarded as more important, some
researchers have suggested exercise-induced metabolic stress is in fact the more
critical factor (Shinohara et al. 1997). Currently, it is unclear which factor is more
important and while it has been definitely established that fatigue (which is the
primary precursor to exercise-induced metabolic stress) is not required for

strength gains (Folland et al. 2002), it is important to note that no similar finding
has yet been made for hypertrophy.
Secondary mechanisms and molecular processes

Metabolic stress is thought to lead to the activation of molecular processes that
cause elevated periods of muscle protein synthesis over muscle protein
breakdown over an extended period of time, ultimately bringing about net protein
accretion. The molecular processes are mediated by a number of key
intermediary steps (called secondary mechanisms), including elevated local
hormone production, muscle damage, ROS production, increased muscle fiber
recruitment, cell swelling (see reviews by Schoenfeld, 2013; Pearson and Hussain,
2014) as well as altered production of myokines (see review by Schoenfeld,
2013), all of which can be linked to increased activity in molecular signalling
processes leading to muscular hypertrophy.
Back to top of section Down to references
-
SECONDARY STIMULI FOR HYPERTROPHY

Introduction
The two primary mechanisms for hypertrophy, mechanical loading and exerciseinduced metabolic stress, lead to various secondary categories of mechanism that
have been theorized to activate molecular signalling processes leading to
elevated muscle protein synthesis, including mechanotransduction, muscular
damage, elevation in systemic and localized hormones, cell swelling, and ROS
production (see review by Pearson and Hussain, 2014), as well as other
mechanisms that may have a role but which have not been as extensively
explored, such as nitric oxide and heat shock proteins.
-
Mechanotransduction
Introduction
Almost all animal cells contain proteins that are inherently capable of detecting
mechanical signals involving deformation of any of the main three components of
the cell membrane (extracellular, bilayer, or cytoskeletal layers) and are therefore
mechanosensitive (see review by Hamill and Martinac, 2001). In the case of
muscle cells, this ability to sense mechanical loading is likely built into the
structures that enable the transfer of force within the cell (in the inner structure,
or cytoskeleton, which includes the chains of sarcomeres) and between the inner
structure and the cell membrane (see review by West et al. 2010a).
Sensitivity to mechanical signals is achieved by the presence of mechanosensitive
proteins situated next to the cell membrane. Consequently, deformation of any
of the three layers of the cell membrane by external forces leads to changes in
the tension, thickness, or local curvature of a layer, which can be detected by the
mechanosensitive proteins. Additionally, where proteins are directly attached to
the cell membrane by cytoskeletal or extracellular attachments between the layer
and the mechanosensitive protein, this can also allow the detection of mechanical
loading to occur (see review by Hamill and Martinac, 2001). Once mechanical
loading has been detected, this leads to alterations in various processes by
means of mechanically-gated ion channels, mechanoreceptors, enzymes,
intracellular calcium ion release, and transmitter release (see review by Hamill
and Martinac, 2001).
Mechanosensors involved in hypertrophic signalling

Currently, it is thought that the magnitude and duration of tensile force within a
muscle fiber are detected by specific sets of mechanosensitive proteins called
mechanosensors and that these mechanosensors are involved in initiating the
process of hypertrophy (see review by Schoenfeld, 2013). There are several
potential candidates for these mechanosensors. West et al. (2010a) suggested
classifying potential candidates in respect of their locations: in the myosin and
elastic filaments, at the costamere and extracellular matrix, and at the
myotendinous junction. To date, most research has focused on the possibilities at
the costamere and extracellular matrix, with integrin-associated focal adhesion
kinase (FAK), paxillin, integrin-linked kinase (ILK-1), and mitogen-activated protein
kinase (MAPK) being the main candidates (see reviews by Carson and Wei, 2000;
Kjaer, 2004; Flck, 2012; Schoenfeld, 2013; Pearson and Hussain, 2014).
Integrin-associated focal adhesion kinase (FAK)

Integrins are proteins that very likely act as mechanoreceptors by virtue of their
attachment to the cell membrane. Integrins are integrated with larger structures
called costameres. Costameres, which are also called sarcolemmal focal adhesion
complexes, link the internal cytoskeleton of the muscle cell (including the
sarcomeres) to the outer cell membrane (see reviews by Carson and Wei, 2000;
Ervasti, 2003; Ingber, 2006). Integrins are thought to cause a cascade of
signalling processes once they have detected changes in the shape of the cell
membrane, including FAK and MAPK (see review by Carson and Wei, 2000).
Integrins are connected to the actin filaments of sarcomeres by specialized
anchoring complexes called focal adhesions, which comprise multiple smaller
proteins (see review by Ingber, 2006). Focal adhesion kinase (FAK) is a tyrosine
kinase that acts on focal adhesions and is phosphorylated quickly after the cell
membrane is deformed (see review by Durieux, 2007). This suggests that FAK is
involved in mechanotransduction subsequent to integrin-related sensing of
external mechanical loading on the muscle cell.
Several studies have reported increases in FAK activity as a result of mechanical
loading in animal models (Flck et al. 1999; Gordon et al. 2001; and Klossner et
al. 2009) and decreases in FAK activity as a result of mechanical unloading (Flck
et al. 1999; Gordon et al. 2001; and Klossner et al. 2009). In addition, Li et al.
(2013) found that FAK activity was significantly reduced as a result of 8 days of
bed rest leading to muscular atrophy but although activity was increased
following a resistance training program leading to muscular hypertrophy, this
increase in FAK was not significant. Additionally, Klossner et al. (2009) observed
increased activity of FAK in concordance with increased activity of p70S6K in a
rodent model, which suggests that FAK may be involved in activating signalling
along the mTOR pathway.
-
Exercise-induced muscle damage

Introduction to muscle damage
Skeletal muscle tissue has an extraordinary ability for self-regeneration following
damage. It can recover its function even when removed, minced and replaced
(see review by Carlson, 2005). It is thought that the processes of muscular injury
and regeneration are similar irrespective of the type and extent of the damage
that is inflicted (see reviews by De Souza and Gottfried, 2013; Jrvinen et al.
2013).
Types of muscle damage

There are various kinds of muscle damage, of which damage subsequent to
mechanical loading is one category. Within the category of muscle damage
subsequent to mechanical loading, there are sub-categories, including contusions,
lacerations and strains (see review by De Souza and Gottfried, 2013). Contusions
are sustained as a result of large compressive forces, such as might occur during
a collision in rugby or American Football, and typically lead to bruising being
observed on the surface of the skin. Lacerations also occur as a result of
compressive forces but in this case the shape of the external implement is such
that the skin, fascia and even muscle itself are penetrated. Strains are incurred as
a result of large tensile (pulling) forces that lead to the muscle being
lengthened further than it was previously accustomed to being stretched (see
review by De Souza and Gottfried, 2013).
Muscle strains are typically graded as mild (first degree), moderate (second
degree), or severe (third degree) (see review by Jrvinen et al. 2000). Mild strains
are defined as a tear of a few muscle fibers, minor swelling and discomfort with
no or only minimal loss of strength and restriction of the movements (see review
by Jrvinen et al. 2000).
Introduction to exercise-induced muscle damage

Exercise-induced muscle damage subsequent to resistance training is
poorly defined in the literature. Since it is caused by the application of tensile
forces, it might be envisaged as a very modest type of mild muscle strain,
although it is noted that some authorities reject this classification on the basis
that exercise-induced muscle damage does not involve the tearing of whole
muscle fibers (see review by Jrvinen et al. 2013). The most common symptoms
associated with exercise-induced muscle damage are delayed onset muscle
soreness (DOMS) and a reduction in force generating capability.
Paulsen et al. (2012) have proposed a system of classifying exercise-induced
muscle damage on the basis of reductions in force generating capabilities (i.e.
deficits). They suggest that mild exercise-induced muscle damage implies a force
deficit of <20% and full recovery in <48 hours. They propose that
moderate exercise-induced muscle damage implies a force deficit of 20 50% and
full recovery in 2 7 days. They propose that severe exercise-induced muscle
damage implies a force deficit of >50% and full recovery in >7 days.
Causes of exercise-induced muscle damage

Exercise-induced muscle damage is thought to occur mainly as a result of
either unaccustomed exercise or eccentric muscle actions (see review by
Schoenfeld, 2012). Exactly why exercise-induced muscle damage is so prevalent
following eccentric muscle actions is still unclear. Originally, it was proposed that
the muscle fiber strain (i.e. relative length change) might be greater during
eccentric muscle actions than during other types of muscle action and that this
could be responsible for the increased level of muscle damage observed (see
review by Fridn and Lieber, 1992). Later, a refined model was put forward in
which it was suggested that eccentric muscle actions lead to the over-stretching
of individual sarcomeres (see review by Proske and Morgan, 2001).
Recently, Panchangam and Herzog (2012) confirmed that sarcomere
overextension does in fact occur. Secondly, they found that it does not lead to
permanent, irreparable damage. Thirdly, they found that where sarcomeres begin
an eccentric muscle action partly lengthened, this leads to an increased risk of
overextension. Therefore, if the sarcomere length non-uniformity theory (Herzog,
2013) holds true and some sarcomeres are naturally more elongated than others
in any given myofibril, then it stands to reason that muscle damage may occur in
those sarcomeres that are overextended during eccentric muscle actions.
Nature of exercise-induced muscle damage
The nature of exercise-induced muscle damage can be considered in two

categories: (1) damage to the sarcomeres, and (2) damage to the excitation
contraction coupling system (see reviews by Morgan and Allen, 1999; Proske and
Morgan, 2001). As described above, damage to sarcomeres could occur
subsequent to myofibrils being overstretched and the most vulnerable individual
sarcomeres being pulled apart (see review by Herzog, 2013). It has been
suggested that damage to the excitationcontraction coupling system could occur
secondarily to this damage to the sarcomeres, particularly where the sarcomeres
respond by increasing in number (sarcomerogenesis). If the increase in length is
substantial, this could allow damage to the surrounding structures of the
sarcoplasmic reticulum and the t-tubules. In turn, this could cause release of
calcium ions, the failure of excitationcontraction coupling, and the subsequent
loss of force production capability (see review by Proske and Morgan, 2001).
Measuring exercise-induced muscle damage

Measuring exercise-induced muscle damage directly is very difficult (see review
by Paulsen et al. 2012). Currently, the only way to measure muscle damage
directly is to perform histological examination of muscle biopsies in order to
identify the presence of disruptions in the cell ultrastructure (see review by
Paulsen et al. 2012). The ultrastructure of a muscle fiber refers to the inner
contents of the muscle cell, including the individual sarcomeres themselves (Au,
2004).
Consequently, a number of indirect measurements have been proposed as proxies
for the underlying damage that has occurred. These include reductions in forcegeneration capability, the presence of delayed onset muscle soreness
(DOMS), and serum levels of creatine kinase (CK). Currently, the use of these
indirect measurements are not accepted to be good indicators of the underlying
muscle damage (see review by Paulsen et al. 2012). Previously, it was believed
that the relationship between DOMS and exercise-induced muscle damage was
very close. However, our understanding of the nature of muscle damage and its
relationship with DOMS has since developed substantially and it is now
appreciated that while there is some association, the two are not identical.
Effects of resistance training on muscle damage
Many studies using direct measurements of muscle damage have shown that
resistance training of varying kinds can lead to exercise-induced muscle damage
at several levels, as shown in the table below.
Study
Fridn
(1981)
Fridn (198
3)
Fridn (198
8)
Roth (1999)
Roth
(2000a)
Type of
study
Acute
Type of
exercise
Type of
damage
Population
Finding
Unclear
Ultrastructura
l
5 males, aged 20
34 years
Disturba
in relati
Acute
Eccentric cycling
Ultrastructura
l
12 males, aged 25
7 years
Damage
displaye
disrupti
to 3 day
Acute
20 x 25-second
sprints at 86% of
200m PR time
Ultrastructura
l
11 elite male
sprinters, aged 17
28 years
Z-band s
abnorma
Chronic
5 sets of 5
20RM
of unilateral leg
extension
Ultrastructura
l
7 young males (aged

20 30 years) and
8 older males (aged
65 75 years)
Post-tra
ultrastru
the norm
Z-line st
disrupti
Chronic
5 sets of 5
20RM
of unilateral leg
extension
Ultrastructura
l
7 young females
(aged 20 30 years)
and 6 older females
(aged 65 75 years)
In the o
displaye
includin
banding
disrupti
Molecular signalling processes

There are several possible mechanisms by which exercise-induced muscle
damage might be an intermediary mechanism leading to activation of the
molecular signalling processes that bring about elevated muscle protein
synthesis, including elevated inflammatory cell signalling, elevated growth factor
signalling, increased satellite cell activity, and cell swelling (see review by
Schoenfeld, 2012). Thus, it has been proposed that exercise-induced muscle
damage may function as an intermediary step between the two primary
mechanisms of mechanical loading and metabolic stress and other secondary
mechanisms, which may account for differences in its placement as a primary or
secondary mechanism (i.e. Schoenfeld, 2010 vs. Pearson and Hussain, 2014).
Phases of inflammation
In general, muscle regeneration following injury involves a tripartite inflammatory
process, comprising damage removal, repair, and remodelling phases (see
reviews by De Souza and Gottfried, 2013; Jrvinen et al. 2013). Certain
elements of this tripartite inflammatory process are thought to be relevant
to hypertrophic signalling processes. However, the extent to which each of these
phases is observed in exercise-induced muscle damage is unclear.
The damage removal phase involves necrosis of the muscle cell in most serious
forms of muscle injury. Necrosis is the death of a cell, where this arises as a result
of external factors such as injury or disease. It results in the uncontrolled release
of the cell contents in the surrounding environment. However, necrosis is
infrequently observed during exercise-induced muscle damage, except where
rhabdomyolysis has occurred or where force producing capacity is reduced for
periods of time >1 week (see reviews by Paulsen et al. 2012; Jrvinen et al.
2013). The damage removal phase also involves inflammatory cytokine or
myokine signalling, which resembles the immune response to infection and which
leads to leukocyte (neutrophil) infiltration (see reviews by Paulsen et al. 2012; De
Souza and Gottfried, 2013). The neutrophils remove the damaged tissue
by phagocytosis and proteolysis (see review by De Souza and Gottfried, 2013). In
contrast with necrosis, far more studies have observed evidence of intracellular
leucocyte accumulation following resistance training exercise (Paulsen et al.
2012).
-
Elevation of systemic and localized hormones

Acute, albeit slightly delayed activation of the mTOR pathway produced by
mechanical loading seems to involve increases in the levels of growth factors (see
reviews by Zanchi et al. 2008; Laplante and Sabatini, 2009; Adegoke et al. 2012;
Pearson and Hussain, 2014) although it is certain that they are not completely
necessary for hypertrophy to occur (Hornberger et al. 2004; Spangenburg et al.
2008; West et al. 2010; West and Phillips, 2012; reviews by Philp et al. 2011;
Yamada et al. 2012).
The study by West et al. (2010) is particularly interesting for an understanding

of the effects of post-exercise hormone levels. West et al. (2010) compared the
long-term effects of two different resistance training conditions using subjects
who trained one arm unilaterally in each condition. In one condition, the subjects
performed only an arm exercise during the workout and in the other condition
they performed arm exercise as well as leg exercise. The arm-and-leg
condition displayed increased circulating levels of anabolic hormones (serum
growth hormone, insulin-like growth factor (IGF-1) and testosterone) while the
arm-only condition did not. Very large differences between the conditions during
workouts were observed in respect of the circulating hormone levels but there
was no difference in the resulting hypertrophy after 15 weeks.
-
Cell swelling
Cell swelling appears to increase protein synthesis and decrease protein
breakdown (see reviews by Schoenfeld, 2012; Pearson and Hussain, 2014). The
reasoning behind the function of cell swelling as a mechanism for causing
hypertrophy is that the temporary increased pressure against the cell membrane
is perceived as a threat to the structural integrity of the cell membrane (see
reviews by Schoenfeld, 2012; Pearson and Hussain, 2014). In response to this
perceived threat, the cell is thought to carry out a signalling response designed
to reinforce its structure (see reviews by Schoenfeld, 2012; Pearson and Hussain,
2014).
While little is known about these potential cell volume sensors, it has been
suggested that they might be associated with integrins (see reviews by
Schoenfeld, 2012; Pearson and Hussain, 2014). Integrins are proteins found in
costameres within muscle fibers. Costameres are the structural components of
muscle cells that connect the myofilaments to the cell membrane, running
perpendicular to the prevailing direction of the sarcomeres. They are therefore
perfectly placed to detect changes in muscular volume, particularly where this
involves increases in diameter. Some preliminary findings have suggested that
the signalling processes that result from cell swelling occur through the mitogen-
activated protein kinase (MAPK) pathway rather than the mTOR pathway (see
review by Pearson and Hussain, 2014), although this research is still at an early
stage.
-
MOLECULAR PROCESSES FOR HYPERTROPHY:

mTOR
Introduction to mTOR
The mechanistic (formerly mammalian) target of rapamycin (mTOR) pathway is
possibly the most important and certainly the most widely-studied pathway
involved in muscular hypertrophy, although several aspects of it are less clear
than we might like to believe (Phillips, 2009). mTOR itself is a protein kinase.
A protein kinase is an enzyme that adds phosphate groups to amino acids (most
commonly serine, threonine, tyrosine or a combination of these) in a process
called phosphorylation, usually by taking these phosphate groups from adenosine
triphosphate (ATP), which is the main source of cellular energy. Phosphorylation
alters the enzyme activity, location or behavior of the phosphorylated protein.
Thus, phosphorylation is a frequently observed feature of many molecular
signalling pathways. mTOR is a serine/threonine kinase (see review by Hay and
Sonenberg, 2004) and can therefore bring about phosphorylation of either of
these amino acids.
Forms of mTOR
mTOR can be found as at least two multi-protein complexes, mTOR complex 1
(mTORC1) and mTOR complex 2 (mTORC2) (see reviews by Laplante and Sabatini,
2009; Marcotte, 2014). While mTOR activity appears to be essential to the
process of muscular hypertrophy (Goodman et al. 2011), in most circumstances, it
is mTORC1 that is sensitive to rapamycin and not mTORC2, as indicated by the
fact that mTORC1-knockout-mice have reduced muscle mass while mTORC2knockout-mice do not (see review by Adegoke et al. 2012).
Inhibition of mTOR
Inhibition of the mTOR pathway by the immunosuppressant drug rapamycin,
which is used to prevent kidney graft rejection (see review by Wang and Proud,
2006), stops the elevation of muscle protein synthesis that occurs subsequent to
mechanical loading (Drummond et al. 2009; Phillips, 2009), the consumption of
amino acids (Dickinson et al. 2011), the administration of clenbuterol (Kline et al.
2007), and the administration of exogenous insulin-like growth factor-1 (IGF-1)
(Rommel et al. 2001).
Activation of mTOR
Introduction
It is currently thought that there are three main branches within the overall mTOR
pathway that are stimulated in different ways: growth factors, mechanoreceptors,
and amino acids.
Growth factors
Currently, it is thought that growth factors arrive at the cell membrane, where
they bind to receptors, which are tyrosine kinases (see review by Marcotte et al.
2014). Through the binding of the growth factors, the tyrosine kinases are
activated and subsequently recruit insulin receptor substrates (IRS1/2), which
brings phosphatidylinositol 3-kinase (PI3K) to the membrane (see review by
Marcotte et al. 2014). PI3K converts phosphoinositol (4,5)-bisphosphate into
phosphoinositol (3,4,5)-trisphosphate, which is a docking site for Akt and 3phosphoinositide-dependent protein kinase-1 (PDK1).
The arrival of both Akt and PDK1 together at this docking site allows PDK1 and
mTORC2 (which is located at the cell membrane) to phosphorylate Akt
together (see review by Marcotte et al. 2014). Akt then phosphorylates mTORC1,
removing proline-rich akt substrate of 40 kDa (PRAS40) from mTOR and removing
tuberous sclerosis complex-2 (TSC2) from Ras homolog enriched in brain
(Rheb). TSC2 is a GTPase-activating protein that turns off Rheb. Rheb is a direct
activator of mTOR. Therefore, switching off TSC2 activates mTOR (West and Baar,
2013).
Although the role of IGF-1 in the signalling processes leading to muscular

hypertrophy has been well-described, it is key to note that IGF-1 signalling is not
at all necessary for hypertrophy to occur (Hornberger et al. 2004; Spangenburg et
al. 2008; West et al. 2010 reviews by Hamilton and Baar, 2008; Philp et al. 2011;
Yamada et al. 2012) and also that the other routes that are taken to mTOR do not
seem to require PI3K.
A splice variant of IGF-1 has been designated as IGF-1Ec but also called mechano
growth factor (MGF). MGF appears to be particularly important for
the hypertrophy that results from stimulation of the growth factor pathway within
the overall mTOR framework (Schlengel et al. 2013).
Mechanoreceptors
Mechanosensors appear to be able to convert mechanical energy into molecular
signals in the mTOR pathway (see reviews by Schoenfeld, 2013; Pearson and
Hussain, 2014). The mechanism by which this occurs is thought to involve a
similar final step to that which is observed in growth factors (the removal of Rheb
from TSC2). Thus, it is expected that the effects of growth factors and mechanical
loading are not additive (see review by Marcotte et al. 2014). However, the
process by which mechanoreceptors activate mTOR seems to differ slightly from
that of growth factors insofar as it happens without involving PI3K or Akt (see
reviews by Philp et al. 2011; Marcotte et al. 2014). It actually appears to
be mediated by either phosphatidic acid (You et al. 2012; Hornberger et al. 2006)
or the behavior of Rheb itself (Jacobs et al. 2013).
Phosphatidic acid is a lipid-based messenger that is dependent upon
phospholipase D enzyme activity, binds the FRB domain of mTOR and activates
p70s6k (Hornberger et al. 2006; reviews by Zanchi et al. 2008; Philp et al. 2011;
Yamada et al. 2012). Overexpression of phospholipase D enzyme activity has
been observed to increase mTOR activity (see review by Laplante and Sabatini,
2009) and mechanical load has also been found to increase production
of phosphatidic acid (see review by Marcotte et al. 2014).
More recently, the important work by Jacobs et al. (2013) has demonstrated that
once a mechanoreceptor detects loading, this switches on a RxRxx-targeted
kinase that phosphorylates TSC2, switches off Rheb, and activates mTOR (West
and Baar, 2013). How this might relate to the elevation of levels of phosphatidic
acid, however, is unclear.
Amino acids (protein)

Amino acids appear to increase mTOR activity through a very
different mechanism from either growth factors or mechanoreceptors (see
reviews by Philp et al. 2011; Marcotte et al. 2014; Bar-Peled and Sabatini, 2014).
Recently, it has become clear that the presence of amino acids in fact
causes mTOR to move in a specific way within cells. When there are no amino
acids, mTOR is widely spread out throughout the cell but when amino acids are
introduced, this causes mTOR to move to the cell membrane, where it forms
mTORC1 with Rheb (see reviews by Philp et al. 2011; Marcotte et al. 2014; BarPeled and Sabatini, 2014; McGlory and Phillips, 2014). At the cell membrane,
there are a number of regulating proteins, including the Ragulator, the tumor
suppressor folliculin and the Rag family of small G-proteins. These regulating
proteins are thought to interact with one another and with both mTORC1 and
Rheb to bring about activation of mTOR.
Effects of mTOR activity

Activity in the mTOR pathway leads to an extended period during which there is
an excess of muscle protein synthesis (also known as mRNA translation) over
muscle protein breakdown and consequently net protein accretion within the
muscle, largely because of increases in muscle protein synthesis (see reviews by
Hay and Sonenberg, 2004; Wang and Proud, 2006; Zanchi et al. 2008; Laplante
and Sabatini, 2009; Marcotte, 2014). mTOR exerts these effects through the
phosphorylation by mTOR of the eukaryotic initiation factor 4E-binding protein
(4E-BP1) and by the phosphorylation of p70S6K1 (also known as S6K1).
The phosphorylation of 4E-BP1 by mTOR causes its dissociation from eukaryotic
translation initiation factor 4E (eIF4E) and stimulates the binding of eIF4A and
eIF4E to eIF4G in order to form the eIF4F complex (see reviews by Sanchez et al.
2014; Kimball, 2014), which is a key first step for mRNA translation (see review by
Egerman and Glass, 2014). Essentially, 4E-BP1 represses mRNA translation and
therefore this process allows the activation of the ribosome and permits an
elevated rate of muscle protein synthesis (see review by Flck, 2012).
The phosphorylation of p70S6K1 by mTOR allows p70S6K1 to phosphorylate
programmed cell death 4 (PDCD4). This releases PDCD4 from eIF4A, which
allows eIF4A to bind with eIF4G in order to form the eIF4F complex (see review by
Kimball, 2014). The eIF4F complex mediates the initiation of mRNA translation.
-
CORRELATIONS WITH HYPERTROPHY: mTOR

PATHWAY
Study
Acute measure
Pathway
Long-term measure
Population
Baar and
Esser
(1999)
Phosphorylation
of p70S6k
mTOR
Muscle mass
Rodent model
Terzis
(2008)
Phosphorylation
of p70S6k
mTOR
Whole body fat-free

mass
8 untrained males
mTOR
Type IIA muscle

fiber cross-sectional
area
8 untrained males
mTOR
Lean body
mass measured by DEXA
scans
15 old and 21 youn

subjects
mTOR
Muscle volume
measured using MRI
scans
18 healthy, untrain
young males aged
years
Muscle fiber area
23 healthy males a
3 years
Terzis
(2008)
Mayhew
(2009)
Phosphorylation
of p70S6k
Phosphorylation
of p70S6k
Mitchell
(2012)
Phosphorylation
of p70S6K
Mitchell
(2013)
Phosphorylation of
p70S6K
mTOR

-
MOLECULAR PROCESSES FOR HYPERTROPHY:

MAPK
Introduction to MAPK
The Mitogen-Activated Protein-Kinase pathway (MAPK) has been less well-studied
for hypertrophy than the mTOR pathway. Nevertheless, it appears to respond to
mechanical loading, making it a primary pathway by which resistance training can
cause hypertrophy. As far as muscles are concerned, the MAPK family of proteins
comprises four distinct signalling pathways: extracellular signal-regulated kinases
1 and 2 (ERK1/2), p38 MAPK, c-Jun NH2-terminal kinases (JNK), and ERK5 (see
reviews by Kramer and Goodyear, 2007; Schoenfeld, 2010).
Activation of MAPK
Although research into the means through which activity in the MAPK pathway
occurs is not as advanced as similar research in the mTOR pathway, it does
appear that ERK1/2 is activated subsequent to almost any type of exercise in
rodent models and in humans (see review by Kramer and Goodyear, 2007) and
that variant forms of p38 MAPK are also activated, particularly in response to
endurance exercise. More intense exercise, particularly where muscle damage
occurs, appears to stimulate JNK. JNK phosphorylation seems to increase linearly
with increasing mechanical load (see review by Kramer and Goodyear, 2007).
It has been suggested that MAPK (ERK1/2, p38 MAPK, and JNK) has a role in
mediating the antioxidant enzyme response to the release of reactive oxygen
species (ROS) in muscles post-exercise (see review by Kramer and Goodyear,
2007). Consequently, it may be that MAPK is activated by exerciseinduced metabolic stress. This has since been further supported
by observations that the signalling processes that result from cell swelling may
occur through the MAPK pathway (see review by Pearson and Hussain, 2014).
-
MOLECULAR PROCESSES FOR

HYPERTROPHY: Calcineurin-NFAT
Introduction to Calcineurin-NFAT pathway

Calcineurin is a serine/threonine phosphatase (a phosphatase is an enzyme that
removes phosphate groups from a target, which is the opposite of the action of
kinases, which phosphorylate their targets). Like the MAPK pathway, the
Calcineurin-NFAT pathway has been less well-studied for hypertrophy than the
mTOR pathway, remains poorly understood, and is rarely discussed in depth (see
review by Hudson and Price, 2013).
Activation of Calcineurin-NFAT
Calcineurin is activated by increasing levels of calcium ions (Ca2+) in the cell
cytoplasm (see review by Hudson and Price, 2013). As a phosphatase,
calcineurin de-phosphorylates the nuclear-factor-of-activated-T-cells (NFAT)
transcription factors, of which there are four: labelled c1c4 (see review by Glass,
2003). This process causes NFATs to move towards the nucleus. Gene expression
in this pathway appears to be regulated through muscle-specific (myocyteenhancing factor 2, myoblast determination protein) and non-specific (NFAT
and GATA-2) transcription factors and may even affect myostatin (see review by
Michel et al. 2007).
There were early indications that calcineurin is necessary for muscular
hypertrophy to occur in response to insulin-like growth factor-1 (IGF-1) (Musar et
al. 1999; Semsarian et al. 1999) and mechanical loading (Dunn et al. 1999).
However, a later report by Parsons et al. (2004) found that calcineurin deficiency
did not impair hypertrophy induced by either mechanical load or IGF-1. A recent
review attempted to address the conflicting reports in the literature (Hudson and
Price, 2013) but was not able to reach a firm conclusion on the key modifying
factors.
-
MOLECULAR PROCESSES REGULATING MUSCLE

MASS: Myostatin
Introduction to myostatin
Myostatin, also known as growth and differentiation factor 8 (GDF-8), is a chalone
protein that regulates muscle mass, affecting both the proliferation and
differentiation of myoblasts (see review by Elkina et al. 2011). Chalone proteins
are hormones that are secreted by organs and that inhibit the growth of those
organs by temporarily preventing cellular mitosis (see reviews by Bullough, 1971;
Marcotte et al. 2014). Myostatin causes hypertrophy when its expression is
reduced and atrophy when its expression is increased (see reviews by Egerman
and Glass, 2014; Rodriguez et al. 2014).
Myostatin and aging

There are some early indications that natural levels of myostatin expression may
be related to the phenomenon of sarcopenia, the age-related loss of muscle mass,
or cachexia, the disease-related loss of muscle mass. Case-control studies
comparing normal and atrophied muscles have found elevated levels of myostatin
where muscle loss has occurred either as a result of age, disuse or disease
(Reardon et al. 2001; Wojcik et al. 2008). Whether such muscle loss is mediated
by the change in myostatin levels or causes the reduction in myostatin levels is
unclear, however.
Effect on muscle mass

When naturally occurring or artificially manipulated mutations are produced in
myostatin genes that lead to its improper function or complete failure, this
causes a massively muscled physique in mammals even at a very young age. This
unusual phenomenon has been observed in a range of different species,
including dogs (Mosher et al. 2007), cows (Grobet et al. 1997) and even humans
(Schuelke et al. 2004). Interestingly, this phenotype also appears to cause a
reduction in adipose tissue but whether this decrease occurs directly as a result of
the action of myostatin or indirectly as a result of the increased muscle mass is
unclear (see review by Elkina et al. 2011).
Effect on muscle strength
Intriguingly, there are indications from mouse models that increasing muscle
mass by blocking myostatin from inhibiting hypertrophy may impair muscular
function by reducing specific force production (Amthor et al. 2007; Personius et al.
2010; Gentry et al. 2011; Mendias et al. 2011; Giannesini et al. 2013; see review
by Smith and Li, 2013). Specific force production is force production per unit
cross-sectional area of the muscle fiber. Thus, where myostatin inhibitors are
developed for therapeutic uses for increasing muscle mass or for enhancing
sporting performance illegally by doping (see reviews by Matsakas and Diel, 2005;
Fischetto and Bermon, 2013), this may not actually improve functional outcomes.
Effect on myonuclear domain size

The reduction of specific force production while increasing muscle mass when
manipulating myostatin has been ascribed to the failure to maintain a constant
myonuclear domain. In a myostatin-deficient mouse model, Qaisar et al. (2012)
measured individual myonuclear domains within single muscle fibers.
They reported that the size of individual myonuclear domains in the
hypertrophied muscle fibers of the myostatin-deficient mice was significantly
correlated with the specific force. This suggests that myostatin deficiency alone
increases the size of the myofiber without concomitantly increasing the number of
myonuclei and that it is able to increase the myonuclear domain past the point
where it can function efficiently.
Activation of myostatin: interactions with satellite cells

It was once believed that myostatin interacted to a great extent with satellite
cells, insofar as it was thought to be essential for keeping them quiescent, and
that blocking myostatin led to satellite cell proliferation and consequently
hypertrophy (see review by Smith and Li, 2013). Now, it has been found that
myostatin appears to act directly on the muscle fiber to produce hypertrophy and
does not act indirectly via satellite cells. Indeed, it is known that myostatin
deficiency causes marked hypertrophy without maintaining a constant
myonuclear domain (Qaisar et al. 2012), which is the main function of satellite
cells. Thus, it has been suggested that this failure to activate satellite cells while
still producing marked hypertrophy is at the heart of why myostatin inhibition
leads to reductions in specific force production (see review by Smith and Li,
2013).
Activation of myostatin: the Smad pathway

Myostatin appears to be able to activate receptors relating to certain transcription
factors called Small Mother of Decapentaplegic (Smad) proteins (see reviews by
Egerman and Glass, 2014; Rodriguez et al. 2014; and Marcotte et al. 2014).
Myostatin binds to either Activin Receptor IIA (ActRIIA) or Activin Receptor IIB
(ActRIIB). This activates either one of the activin type I receptors Activin-Like
Kinase-4 (ALK-4) or 5 (ALK-5), which in turn causes the phosphorylation of Smad2
and Smad3, which then bind with Smad4. As noted above, the Smad proteins are
transcription factors and when bound in this way they migrate to the nucleus and
act on their key target genes, which include MyoD, Myf5 and myogenin (see
reviews by Elkina et al. 2011; Egerman and Glass, 2014; Rodriguez et al. 2014;
and Marcotte et al. 2014).
Activation of myostatin: the mTOR pathway

There is a currently a general consensus that there are interactions between the
mTOR pathway and the myostatin-smad pathway, although the nature of such
interactions is as yet unclear (see reviews by Elkina et al. 2011; Egerman and
Glass, 2014; Rodriguez et al. 2014; and Marcotte et al. 2014). Studies appear to
demonstrate that the mTOR pathway us activated in the absence of myostatin
and inhibited in the presence of myostatin (see reviews by Egerman and Glass,
2014; Rodriguez et al. 2014; and Marcotte et al. 2014).
Effects of resistance training

Most studies comparing the effects of short-term and longterm resistance training programs have found reductions in myostatin
gene expression, irrespective of the population tested and the type of
resistance training program used.
The following table sets out studies that have assessed changes in myostatin
gene expression following short-term (acute) and long-term (chronic) resistance
training interventions.
Study
Kim (2005)
Trial
type
Acute
Duration
Protocol
Population
1 session
3 sets of 8 12 repetitions to
muscular failure of the squat, leg
press, knee extension exercises
20 young subjects,
(10 females and 10
subjects, aged 60
and 9 males)
8 young females, a
6 older females, ag
Raue
(2006)
Acute
1 session
Bilateral knee extensions for 3 sets

of 10 repetitions with 70% of 1RM
Hulmi
(2007)
Acute
1 session
Bilateral leg press exercise for 5

sets of 10RM
11 untrained health
aged 62.3 6.3 yea

sets of 10RM
18 resistance-traine
either protein (9 su
4.3 years) or a pl
aged 62.1 4.2 yea

sets of 10RM
38 subjects: 13 rec
5.2 years and 14 re
27.2 3.0 years
1 session

sets of 10RM
29 subjects: 9 rece
5.0 years and 9 rec
a placebo: 27.4 3
Acute
6 sessions
over 6 days
Maximum voluntary isokinetic

eccentric contractions for 6 sets of
15 repetitions
15 young, untraine
Dalbo
(2011)
Acute
2 sessions
over 48
hours
3 sets of 10 repetitions with 80% of

on 1RM of the leg press, hack
squat, and leg extension exercises
10 younger males,
10 older males, age
Roth
(2003)
Chronic
9 weeks
Unilateral knee extension

resistance training
15 young and older

and 8 females)
21 weeks
Bilateral leg press, bilateral knee

extension, and bilateral knee
flexion for 2 5 sets of 5 20
repetitions with 40 85% of 1RM
11 untrained health
aged 62.3 6.3 yea
21 weeks

sets of 10RM
38 subjects: 13 rec
5.2 years and 14 re
27.2 3.0 years
12 weeks
2 sets of 20 repetitions on the

unilateral leg press, leg extension
and leg curl machines
15 individuals with
stroke (10 males an
76 years
Hulmi
(2008)
Hulmi
(2009)
Hulmi
(2009a)
Costa
(2007)
Hulmi
(2007)
Hulmi
(2009)
Ryan
(2011)
Acute
Acute
Acute
Chronic
Chronic
Chronic
1 session
1 session
Study
Laurentino
(2012)
Laurentino
(2012)
Trial
type
Chronic
Chronic
Duration
Protocol
Population
8 weeks
Heavy-load resistance training

(80% of 1RM)
9 physically active
8 weeks
Light-load resistance training (20%

of 1RM) combined with BFR
10 physically active
Effects of myostatin blockers

Introduction
As Matsakas and Diel (2005) have explained, there are three basic ways in which
myostatin can be blocked from its normal function. Firstly, as has been
demonstrated in animal models, researchers can knock out the gene. This leads
to the breeding of animals that are deficient in the ability to produce myostatin
naturally. Secondly, in normal animals, myostatin signalling can be chemically
inhibited by stopping the myostatin protein from becoming activated. Thirdly, in
normal animals, myostatin signalling can be chemically inhibited by stopping
it binding to its receptor, most commonly by the production of specific antibodies
(see review by Matsakas and Diel, 2005).
MYO-029
Research has been conducted into a small number of different myostatin
inhibitors in both animals and in humans in order find treatments for cachexia,
muscular dystrophies, and sarcopenia (see review by Smith and Li, 2013). In
humans, Wagner et al. (2008) performed a double-blind, randomized, placebocontrolled study in 116 subjects with muscular dystrophy in order to assess the
safety of two different doses of MYO-029 (1mg, 3mg, 10mg, and 30mg per kg of
bodyweight), a myostatin antibody. The researchers found that all doses of MYO029 displayed good safety and tolerability with the exception of allergic skin
rashes being observed with doses >10mg per kg of bodyweight. Although the
primary outcome of the study was not muscle size, the researchers did report a
trend towards increased muscle mass, as measured using dual-energy
radiographic absorptiometry (DEXA). Jameson et al. (2012) performed a
preliminary clinical trial of LY2495655, which is a myostatin antibody

undergoing development for cancer cachexia. This drug was reported to be welltolerated by in advanced cancer patients at a range of doses and was associated
with an increase in leg muscle volume.
ACE-031
Research has been conducted into a small number of myostatin inhibitors in both
animals and in humans in order find treatments for cachexia, muscular
dystrophies, and sarcopenia (see review by Smith and Li, 2013). In humans,
Campbell et al. (2012) performed a double-blind, placebo-controlled study to
assess the safety of two doses (0.5 and 1mg per kg of bodyweight) of ACE-031 (a
soluble form of activin receptor type IIB), which binds to myostatin and other
negative regulators of muscle mass. The population tested comprised cohorts
of boys with Duchenne muscular dystrophy (mean age: 10.3 years). The
researchers reported no severe adverse events although there were reversible
nosebleeds and the spontaneous appearance of telangiectasias (dilated blood
vessels in the skin). Nevertheless, total lean body mass as measured by DEXA
increased significantly and thigh muscle volume displayed a trend in the same
direction. Attie et al. (2013) similarly performed a double-blind, placebo-controlled
study to assess the safety of much lower doses (0.02 0.03mg per kg of
bodyweight) of ACE-031 in 48 healthy, postmenopausal women randomized to
receive 1 dose of ACE-031. The researchers found that this dose was generally
much more well-tolerated although there was some reddening of the skin in some
subjects at the sites used for injections. Significant increases in total lean body
mass and thigh muscle volume were still observed.
-
MOLECULAR PROCESSES REGULATING MUSCLE

MASS: Satellite cells
Introduction to satellite cells
Satellite cells are so called because they are located on a niche in the surface
of muscle cells between the cell membrane of the muscle fiber (i.e. the
sarcolemma) and the basal lamina. The basal lamina is the internal side of a twopart layer of extracellular matrix material called the basement membrane, which
wraps around the muscle fiber (see review by Sanes, 2003).
Although only recently coming to the fore of hypertrophy research, satellite cells
were actually discovered over 50 years ago (Mauro, 1961). Satellite cells are
relatively inactive (called quiescent) under normal circumstances (see reviews
by Charg and Rudnicki, 2004; Relaix and Zammit, 2012; Yin et al. 2013; Blaauw
and Reggiani, 2014). As a result, they themselves have a very high large nuclearto-cytoplasmic ratio, smaller nuclei, and a reduced amount of organelles (see
reviews by Charg and Rudnicki, 2004; Yin et al. 2013).
Satellite cells, which are also called muscle precursor cells (Kadi et al. 2004a) or
myogenic stem cells (Schoenfeld, 2010), are found in all muscle groups and in all
types of muscle fiber, although populations of satellite cells are not always equal
in all places. Greater concentrations of satellite cells have been noted particularly
near motor neuron junctions and near capillaries within muscles. (see reviews
by Charg and Rudnicki, 2004; Montarras et al. 2013). Satellite cells can be
identified by the expression of the Paired Type Homeobox transcription factor
(Pax7) which has been identified as a key marker for both quiescent and activated
satellite cells (see review by Motohashi and Asakura, 2014).
Satellite cell populations and aging

Some (Renault et al. 2002; Kadi et al. 2004) but not all (Roth et al. 2000)
researchers have identified that the population of satellite cells may reduce with
increasing age in humans. Additionally, some (Dreyer et al. 2006) but not all (Roth
et al. 2001) researchers have observed that the satellite cell response to a single
bout of training is lower in elderly compared to younger individuals. In an attempt
to explain these varied findings, it has been suggested that the differences
between trials may arise because of inter-individual variability in the muscle fiber
type, as some investigations have revealed that aging results in deficiencies in
satellite cell populations specifically in type II (fast twitch) muscle fibers (Verdijk
et al. 2007; Verdijk et al. 2014). However, it appears that these age-related
deficits can be fully reversed in the elderly by as little as 3 months of resistance
training (see review by Kadi et al. 2005; Verdijk et al. 2014).
Satellite cell responses and hypertrophy

Introduction
Hypertrophy of a muscle fiber can occur either by increasing the protein content
associated with existing nuclei or by the addition of new nuclei (see reviews
by Charg and Rudnicki, 2004; Relaix and Zammit, 2012; Yin et al. 2013; Blaauw
and Reggiani, 2014). Since muscle cells are post-mitotic and myonuclei are
therefore unable to divide in order to increase their number, where new nuclei are
required, these must come from outside. Satellite cells are believed to provide the
necessary nuclei as required following damage to the muscle fiber.
Correlations
Although it is currently an unresolved issue whether satellite cell activity is
required for hypertrophy to occur (see review by Blaauw and Reggiani, 2014),
some researchers have investigated the relationships between satellite cell
responses and hypertrophy. Most importantly, Bellamy et al. (2014) reported that
the satellite cell response over 24 72 hours to a single bout of training was
strongly associated with the hypertrophy resulting from a similar 16-week lowerbody resistance training program (R-squared = 57%), as measured by MRI scans
of the quadriceps. This indicates that individuals who have the greatest pool of
available satellite cells at the onset of a resistance training program are those
who are able to display the greatest increases in muscular size as a result of
training.
Requirement for satellite cells

Whether satellite cells are essential for hypertrophy to occur has historically been
debated extensively over many years, with positions being taken at both
extremes (see review by Blaauw and Reggiani, 2014). Even recent studies appear
very polarised, with some defending the proposal that marked hypertrophy is
possible even where the majority of satellite cells have been depleted (McCarthy
et al. 2011) and others claiming to refute it (Murphy et al. 2011).
Myonuclear domain size

One of the key factors in the discussion is whether myonuclear domain size must
be maintained at a constant level. If this is the case, it would support the need for
satellite cells in the hypertrophic process. Indeed, early research suggested that
the myonuclear domain size was relatively constant (Allen et al. 1999). However,
more recent work has challenged this assumption and has shown neither constant
ratios between numbers of myonuclei and muscle fiber size (Bruusgaard et al.
2006) nor concomitant increases in myonuclei and muscle size (Blaauw et al.
2009).
Satellite cell populations and atrophy

A very interesting recent development in the research into satellite cells has been
the discovery that muscle disuse atrophy does not cause a reduction in satellite
cell populations (Snijders et al. 2014). In a trial involving single-leg knee
immobilisation with a cast for a 2-week period, the researchers observed a
substantial reduction in muscular size (as measured using CT scans) of 8 2%
and in muscular strength of 23 3% but there was no concomitant reduction in
satellite cell populations in either type I or type II muscle fibers. This suggests
that if the myonuclear domain is indeed an important factor for hypertrophy, then
it is a one-way street.
Satellite cell responses and resistance training

Most studies comparing the effects of chronic resistance training
programs have found increases in satellite cell numbers, irrespective of
the population tested and the type of resistance training program used.
The following table sets out studies that have assessed changes in satellite cell
numbers following long-term (chronic) resistance training interventions.
Study
Trial
type
Duration
Population
Kadi (2000)
Chronic
9 weeks
10 female subjects
Roth (2001)
Chronic
9 weeks
14 young subjects, aged 20-30 years (7 males and 7 female

older subjects, aged 65 75 years (8 males and 7 females)
Study
Trial
type
Duration
Population
Kadi
(2004a)
Chronic
12 weeks
15 young males, aged 24 1 years
Petrella
(2006)
Chronic
16 weeks
26 young subjects (27.0 1 years) and 26 older subjects (63

years)
Olsen (2006)
Chronic
16 weeks
41 male subjects, aged 19 28 years
Mackey
(2007)
Chronic
12 weeks
29 elderly subjects (13 males and 16 females) aged 76 3 y
Verney
(2008)
Chronic
14 weeks
10 active, elderly males
Mackey
(2011)
Chronic
12 weeks
12 young males, aged 25 3 years
Mackey
(2011a)
Chronic
12 weeks
42 females with trapezius myalgia, aged 44 8 years
Nielsen
(2012)
Chronic
19 days
10 male subjects, aged 22.8 2.3 years
Hanssen
(2013)
Chronic
11 weeks
21 healthy, untrained males
Activation of satellite cells

Introduction
When a muscle fiber is damaged, satellite cells all along the muscle fiber are
activated, proliferate and migrate to the site of injury (Schultz et al. 1985). When
satellite cells activate and proliferate, they are referred to as myogenic precursor
cells or myoblasts (see review by Charg and Rudnicki, 2004). These changes are
associated with marked upregulation of the myogenic regulatory factors (MRFs)
Myf5 and MyoD. After activation and proliferation, the myoblasts then terminally
differentiate and fuse to the damaged muscle fiber. This phase is associated with
marked upregulation of the MRFs Myogenin and MRF4 (see review by Charg and
Rudnicki, 2004). Various regulatory pathways are thought to be involved in
the processes of satellite activation and proliferation, operating at three levels:
the satellite cell, the myofiber, and the extracellular matrix (see review by Yin et
al. 2013).
The satellite cell

Several pathways have been researched extensively in relation to the activation
of satellite cells at the level of the satellite cell itself, including Notch, canonical
WNT/-catenin, and sphingolipids (see reviews by Yin et al. 2013; Montarras et al.
2013). Notch signalling is complex and poorly understood. It has been
suggested that the primary role of Notch signalling in relation to satellite cells is
to maintain their quiescence when they are not needed to enter the cell cycle
(see review by Montarras et al. 2013), which would imply that the effect of
reducing Notch signalling is to produce satellite cell proliferation. However, it has
been noted in animal models that Notch signalling may be implicated in both
proliferation and differentiation of satellite cells, which is suggestive of a much
wider and more complex role (see review by Motohashi and Asakura, 2014).
Canonical WNT/-catenin signalling (see review by Huelsken and Behrens, 2002)
is thought to bring about either satellite cell proliferation (see review by
Motohashi and Asakura, 2014) or differentiation after Notch signalling has caused
proliferation (see review by Montarras et al. 2013).
Sphingolipids are bioactive lipids that have important roles in molecular signalling
processes. Sphingolipid signalling appears to be involved in the proliferation of
satellite cells through interactions with the plasma membrane of the
activated cells, although the precise nature of this pathway is not well understood
(see reviews by Hannun and Obeid, 2008; Montarras et al. 2013).
The myofiber
The SDF-1 pathway appears to regulate satellite cell activation. Myofibers secrete
SDF-1, which acts on a receptor located on the surface of satellite cells
called CXCR4. When SDF-1 interacts with the CXCR4 receptor, this leads to the
migration of satellite cells (see review by Yin et al. 2013).
The extracellular matrix

Satellite cells are located on a niche in the surface of muscle cells between the
plasma membrane of the muscle fiber (i.e. the sarcolemma) and the basal lamina.
The basal lamina is the internal side of a two-part layer of extracellular matrix
material called the basement membrane, which wraps around the muscle fiber
(see review by Sanes, 2003). Satellite cells therefore come directly into contact
with the basal lamina of the myofiber, which has a large number of integrin
binding sites. These sites are likely key for converting extracellular mechanical
force into intracellular chemical signals (see reviews by Yin et al. 2013; Montarras
et al. 2013).
-
NET PROTEIN ACCRETION

Introduction
As described above, the activation of certain molecular processes leads
to elevated periods of muscle protein synthesis over muscle protein breakdown
over an extended period of time, ultimately bringing about net protein accretion
(see review by Kumar et al. 2009). The main driver in this process is thought to be
elevated muscle protein synthesis, which appears to change to a much greater
extent that muscle protein breakdown (see reviews by McGlory and Phillips, 2014;
Watson and Baar, 2014).
Correlations with hypertrophy

Acute changes in muscle protein synthesis are not well correlated with long-term
increases in muscle size (Mayhew et al. 2009; Mitchell et al. 2014; review by
Mitchell et al. 2014a), as shown in the table below. This surprising result may
be the cause of the observable inter-individual variability in the long-term
increases in muscle mass (see review by Mitchell et al. 2014a), which is very large
and which have been reported by previous studies (Hubal et el. 2005; Bamman et
al. 2007; review by Timmons, 2011). The causes of this inter-individual variability
are currently unknown but may include genetic factors as well as environmental
factors (e.g. age, habitual levels of physical activity, and training status) (see
review by Mitchell et al. 2014a). Alternatively, it may result from changes in the
muscle protein synthesis response to resistance training, such that the initial
acute response differs substantially from later responses during a resistance

training program (Davidsen et al. 2011; review by Mitchell et al. 2014a).
-
CORRELATIONS WITH HYPERTROPHY

Study
Acute measure
Long-term measure
Duration
Population
Mayhew
(2009)
Muscle protein
synthesis
Lean body mass measured

by DEXA scans
16 weeks
15 old and 21
subjects
Mitchell
(2014)
Muscle protein
synthesis
Muscle volume
(quadriceps) using MRI
scans
16 weeks
23 young male
24 1 years
Protein synthesis
Protein synthesis (also referred to as messenger ribonucleic (mRNA) translation or
simply translation) involves the sequential decoding of mRNA into a protein and
the formation of peptide bonds linking the individual amino acids of this protein.
This process takes place upon the ribosome, which acts as an enzyme
and catalyzes the formation of the new peptide bonds (see reviews by Wang and
Proud, 2006; Flck, 2012).
Ribosomes are complex cellular machines comprising four different ribosomal
RNAs (rRNAs) and approximately 90 different proteins (called r proteins). Protein
synthesis involves three key stages (initiation, elongation, and termination) and
each stage requires the involvement of various external factors, which typically
necessitates changes in their phosphorylation (see review by Wang and Proud,
2006).
Muscle protein synthesis and resistance training

Various studies have found that resistance training produces robust acute
increases in muscle protein synthesis. Increases have been observed with both
heavy loads (Wilkinson et al. 2008; Kumar et al. 2009; Moore et al. 2009; Holm et
al. 2010) and with light loads in combination with blood flow restriction (Fujita et
al. 2007) but largely not with light loads (Fujita et al. 2007; Kumar et al. 2009;
Holm et al. 2010).
When comparing the effects of different loads and protocols on muscle protein
synthesis, resistance training with heavy loads has been found to lead to superior
increases than light loads (Kumar et al. 2009; Holm et al. 2010) and training with
blood flow restriction has been found to lead to superior increases to the same
(light) load without vascular occlusion (Fujita et al. 2007). The effect of load on
muscle protein synthesis appears to display a stepwise increase, with an
upper threshold being observed at around 60% of 1RM (Bowtell et al. 2003;
Kumar et al. 2009).
It has been suggested that differences in the extent to which muscle protein
synthesis is elevated in a muscle post-exercise may be responsible for the lack of
hypertrophy that is sometimes observed. For example, Trappe et al. (2004)
investigated whether the soleus muscles would display small levels of muscle
protein synthesis post-exercise, as the calf muscles are notoriously difficult to
hypertrophy. However, this study did not directly compare muscle protein
synthesis changes in the soleus with rates in other muscles. When the study was
repeated comparing the soleus with the triceps brachii and vastus lateralis, the
differences between muscles were found to be statistically significant but
clinically not meaningful (Mittendorfer et al. 2005), implying that differences in
muscle protein synthesis are not responsible for differences in the rate at which
different muscles experience hypertrophy.
mTOR involvement in muscle protein synthesis

Many studies have shown that the mTOR pathway is key for elevating muscle
protein synthesis (see review by McGlory and Phillips, 2014), although the activity
of the signalling molecules within this pathway do not always correlate with the
resulting levels of muscle protein synthesis (Areta et al. 2013; Mitchell et al.
2014). A number of potential explanations have been proposed for this
discrepancy (see review by McGlory and Phillips, 2014), including observable
variability in the time course and magnitude of different signals, differences in the
methods used to quantify the phosphorylation of the signalling molecules
(Western blotting) and of muscle protein synthesis (quantitative mass

spectrometry), and the fact that these proteins play a number of roles in human
biology and are not simply active in the single function of elevating muscle
protein synthesis (see review by Shimobayashi and Hall, 2014).
-

When drawing inferences from short-term trials, it is
important to note that changes in the phosphorylation of
p70S6k have displayed good correlations with long-term
hypertrophy.
-
GENETICS
PURPOSE
This section describes the current state of the research in respect of
identifying those genetic polymorphisms that are associated with having
(1) a greater amount of muscle mass, and (2) the ability to increase
muscular size to a greater extent with resistance training.
-
BRIEF OVERVIEW
Introduction
Some individuals respond very well to resistance training and display marked
hypertrophy (i.e. responders) while others fail to respond in a meaningful way (i.e.
non-responders) even though they are all subject to to the same training program
(Hubal et al. 2005; Bamman et al. 2007; review by Timmons, 2011). This
considerable inter-individual variability in hypertrophy has been ascribed to

genetic influences, among other things. However, until very recently, the
technology was not available to allow researchers to investigate this proposal
properly.
In addition, some individuals seem naturally to display a higher degree of
hypertrophy during development, resulting in more muscle mass in adulthood
than others of the same height and gender, even when put in the same
environment. The methods for exploring the precise genetic influences on muscle
mass have been similarly limited until recently. However, methods for
investigating the extent to which heritability influences muscle mass in adulthood
have been available for longer, by virtue of twin studies.
Variability in hypertrophy: development

Some reviewers have suggested that genetic factors are responsible for around
50 80% of the inter-individual variability in muscular size (Puthucheary et al.
2011), predominantly as a result of analysis of twin studies (e.g. Seeman et al.
1996; Arden and Spector, 1997; and Nguyen et al. 1998). Whether such trials are
able to control adequately for differences in the lifestyle of the individuals
involved is unknown, however.
Variability in hypertrophy: in resistance training

Since methods have only recently become available for investigating the effect of
genetic polymorphisms on the hypertrophic response to resistance training, there
has been little research performed to date. Indeed, as recently as the 2006-07
update to The Human Gene Map for Performance and Health-Related Fitness
Phenotypes, there was very little research that had been performed to shed any
light on the hypertrophic response to resistance training (Bray et al. 2009).
Nevertheless, some researchers have since found that a small number of different
genetic traits and single nucleotide polymorphisms (SNPs) may be related to a
superior increase in muscle mass, which are set out in the table below.
Many of the recent trials in the table below have made use of data recorded by
the Functional Single Nucleotide Polymorphisms Associated with Human Muscle
Size and Strength (FAMuSS), which is the same data set that was used to produce
the now deservedly famous investigation into the inter-individual responses to
resistance training by Hubal et al. (2005). Recently, a summary of the findings
from this data set was produced by the researchers working on the FAMuSS study
data (Pescatello et al. 2013). The reviewers reported on the results published in
relation to 17 different genes that were specifically tested for their association
with muscle strength or size (Pescatello et al. 2013). They concluded that with a
few minor exceptions, single variants in genetic polymorphisms appear to explain
only minor inter-individual variability in the hypertrophic response to resistance
training (see review by Pescatello et al. 2013).
Variability in satellite cell responses

Some of the variability in hypertrophy resulting from resistance training may arise
from inter-individual differences in the acute or long-term satellite cell response.
Petrella et al. (2008) grouped 66 subjects into extreme responder (17 subjects),
modest responder (32 subjects), and non-responder groups (17 subjects) based
on their average increases in muscular size (58%, 28% and 0%, respectively)
following a 16-week lower-body resistance training program. The satellite cell
population pre-training was greater in the extreme responder group than in either
of the other two groups. Moreover, the satellite cell number increased
significantly from pre- to post-training only in the extreme responder group (by
117%) and not in the other two groups (Bamman et al. 2007; Petrella et al. 2008).
-
GENETIC INFLUENCES ON HYPERTROPHY

Study
Acute measure
Long-term
measure
Duration
Population
Ivey (2000)
Lys 153 Arg

polymorphism in the
myostatin gene
Quadriceps
muscle volume, as
measured by MRI
scans
9 weeks
11 young males,
years, 11 young
aged 20 30 yea
males, aged 65
and 11 older fem
aged 65 75 yea
Thomis (2004)
Myostatin AluI A55T
Muscle cross-
10 weeks
57 males, aged
Acute measure
Long-term
measure
(exon 1), BanII K153R,

TaqI E164 K and BstNI
P198A (all in exon 2)
markers
sectional area of
the upper arm
using CT scans
Riechman (2004
)
SNPs in the interleukin15 receptor-alpha gene

(IL15RA)
Lean body mass

measured by
hydrostatic
weighing
Pescatello
(2006)
Angiotensin I-Converting
Enzyme (ACE) insertion
(I)/deletion (D)
polymorphism (ACE ID)
Muscle volume
(upper arm)
measured with
MRI scans
Polymorphisms in the
resistin gene
Muscle volume
(upper arm)
measured with
MRI scans
SNPs in the IL15RA and

IL-15 genes
Muscle volume
(upper arm)
measured with
MRI scans
Devaney (2009)
A common A to C SNP in
the BMP2 gene (rs15705,
+A1123C)
Muscle volume
(upper arm)
measured with
MRI scans
Kostek (2009)
Myostatin 2379 A > G

and 163 G > A and
follistatin -5003 A > T
and -833 G > T SNPs
Muscle volume
(upper arm)
measured with
MRI scans
Variants in the CCL2 and

CCR2 genes
Muscle volume
(upper arm)
measured with
MRI scans
Van Deveire
(2012)
Ankyrin repeat domain 6

(ANKRD6) SNPs
Muscle volume
(upper arm)
measured with
MRI scans
Li (2014)
A55T polymorphism of
MSTN
Study
Pistilli (2007)
Pistilli (2008)
Harmon (2010)
Muscle thickness
(biceps and
quadriceps)
Duration
Population
years
10 weeks
153 untrained su
males and 77 fe
12 weeks
631 healthy sub

aged 18 41 yea
males and 366 f
12 weeks
409 healthy sub

18 41 years
12 weeks
722 healthy sub

18 41 years (43
and 290 males)
12 weeks
517 healthy sub

aged 18 41 yea
males and 320 f
12 weeks
645 healthy sub

aged 18 41 yea
12 weeks
874 healthy sub

40 years (360 m
and 514 females
12 weeks
922 healthy sub

41 years (376 m
and 546 females
8 weeks
94 healthy, untr
Chinese males
Study
Acute measure
Long-term
measure
Li (2014)
K153R polymorphism of
MSTN
Muscle thickness
(biceps and
quadriceps)
Duration
Population
8 weeks
94 healthy, untr
Chinese males

Genetics appear to play an important role in
differentiating between individuals who display very
marked hypertrophy (responders) and those who do not
(non-responders). However, we are currently unable to
identify those genes or groups of genes that are
associated with responsive or non-responsive tendencies

Hypertrophy

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Hypertrophy

Enviado por

Direitos autorais:

Formatos disponíveis

Hypertrophy

Hypertrophy is an increase in muscular size. Research comparing the

Relative load (percentage of 1RM)

Frequency (whole body or split)

Rest period duration

Bar speed (time under tension)

Muscle action (variable)

10. Muscle action (constant load)

strength sports as it contributes to performance. For example, Brechue et al.

Relationship between muscle mass and strength

Training methods for hypertrophy

Current guidance for hypertrophy

Long-term trials measuring hypertrophy

Short-term trials measuring hypertrophy

Lay-out of this hypertrophy review

SUMMARY EVIDENCE FOR HYPERTROPHY

Long-term study findings for hypertrophy

Multiple sets for volume may cause hypertrophy

Higher volume-matched frequency may cause hypertrophy

Eccentric may cause hypertrophy than concentric

Eccentric may cause hypertrophy than concentric

Non-linear vs. linear

Linear vs. reverse

Linear periodization may cause hypertrophy than reverse linear

Long-term study findings for hypertrophy

SUMMARY EVIDENCE FOR HYPERTROPHY

Long-term study findings for hypertrophy

Heavier loads (<15RM) may cause hypertrophy than light loads

Many relevant studies

Multiple sets for volume may cause hypertrophy

Few relevant studies

Closer to muscular failure may cause hypertrophy

Few relevant studies

Few relevant studies

Few relevant studies

Larger ROM may cause hypertrophy than shorter ROM

Eccentric may cause hypertrophy than concentric

No difference between eccentric and concentric

Few relevant studies

Periodization may cause hypertrophy

Few relevant studies

Non-linear may cause hypertrophy

CONCLUSIONS FOR HYPERTROPHY

Back to top Down to references

This section explores whether training with a conventionally heavy load

Heavy, moderate and light relative loads

(Schoenfeld, 2013), >60% of 1RM (Schoenfeld, 2013), >65% (McDonagh and

MECHANISMS OF HYPERTROPHY IN RELATION TO

Conceptual basis for hypertrophy

thereby create a larger hypertrophic stimulus. Firstly, a greater relative load is

Metabolic stress (more detail)

Molecular signalling for hypertrophy

7 protocols ranging from

Linear relationship between p54 JNK phosphorylation and

Maximal vs. sub-maximal

Maximal displayed greater increases in the phosphorylatio

High load (4 sets of 810

13 recreationally active but

No difference in mRNA expression of myogenic regulatory

High load (6 sets of

Two groups (25 each) of

Muscular failure with 90%

15 recreationally active but

Light to failure displayed increased phosphorylation of Erk